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Clinical Review Report: Cysteamine delayed-release capsules (Procysbi): Horizon Pharma Ireland Ltd. Indication: For the treatment of nephropathic cystinosis [Internet] Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018 Feb.

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Clinical Review Report: Cysteamine delayed-release capsules (Procysbi): Horizon Pharma Ireland Ltd. Indication: For the treatment of nephropathic cystinosis [Internet]

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Appendix 5Summary of Studies Without Control Groups

Aim

To summarize the details and findings of the ongoing RP103-03 extension study, RP103-0456 and an ongoing open-label study, RP103-07.17

Findings

Study Design

RP103-04

This extension study was an open-label, single-arm trial designed to evaluate the efficacy, safety, and tolerability of delayed-release cysteamine in adult and pediatric patients with cystinosis. Secondary objectives assessed long-term quality of life and pharmacokinetics. The study design, populations, treatments, and outcomes are summarized in Table 13.

Patients who had completed study RP103-03 were eligible for RP103-04. These patients were required to complete a minimum of six consecutive monthly visits followed by quarterly visits throughout their participation in the study. New patients (≤ 6 years of age, or had received a kidney transplant; both had to have previously been on a stable dose of Cystagon for at least 21 days) could also be enrolled if they attended a screening visit within 28 days prior to day 1 of the study, followed by a dose confirmation period for five days, in accordance with plasma cysteamine and WBC cystine levels.

RP103-07

This phase IIIb study was an open-label, single-arm, switch trial designed to test safety, tolerability and effectiveness of RP103 following switch from Cystagon in pediatric and adult patients (≥ 12 years of age) with nephropathic cystinosis in the US and European Union. The primary objective of the study was to compare Cystagon and RP103 at steady state WBC cystine levels evaluated after three months and to assess the long-term safety and tolerability of RP103 in patients with cystinosis.17,57

The study consisted of a one week screening period, followed by a three-month Cystagon treatment phase, followed immediately by a four-month RP103 treatment phase (Figure 3). Thereafter, patients who had completed the total seven-month treatment phase could continue to receive RP103 in the long-term phase of the study.17,57

Figure 3. Study Design of RP103-07.

Figure 3Study Design of RP103-07

DR = delayed-release.

Source: Clinical Summary17

Population Demographics and Baseline Disease Characteristics

RP103-04

Demographic and baseline disease characteristics for RP103-treated patients who participated in study RP103-04 are described in Table 14.

A total of 60 patients were enrolled in RP103-04, 40 of whom participated in study RP103-03, and 20 of whom were newly enrolled. Of the 20 newly enrolled patients, 14 were less than or equal to six years of age and six had previously undergone renal transplantation. The overall mean age at start of treatment was 10.9 years (range 2 years to 32 years) and 61.7% were male.17,56

RP103-07

The population characteristics for this study are summarized in Table 15. The study recruited 41 patients older than the age of 12 years, with a mean age of 24.5 years, and 48.8% of patients were male.57

Intervention

RP103-04

Patients who had completed study RP 103-03 continued to receive open-label RP103 at the same dose every 12 hours in study RP103-04 from the time of the last dose prescribed in RP103-03. These patients were then required to complete a minimum of six consecutive monthly visits in RP103-04, followed by quarterly visits thereafter, throughout their participation in the study.17,56

Patients who were newly enrolled attended a screening visit within 28 days prior to day 1 of the study, followed by a dose confirmation period, which took place from day 1 to day 5 of the study, and during which trough cysteamine and peak WBC cystine levels were drawn. The day 1 visit was performed in the morning under fasting conditions, where patients received their first dose of RP103 every 12 hours, at a starting dose equal to 70% of the total daily Cystagon dose at the day of screening. Thereafter, patients attended quarterly follow-up visits throughout their participation in the study.17,56

The investigator was responsible for reviewing plasma cysteamine and WBC cystine levels and safety data prior to scheduled visits to determine any need for dose adjustment for RP103. Patients who did not achieve a target WBC cystine of less than and equal to 1 nmol half cystine/mg protein, or who did not tolerate their dose as determined by the investigator, were to have their RP103 dose adjusted or be terminated from the study.56

RP103-07

All patients participating in RP103-07 completed a seven-day screening period leading up to day 1, when study eligibility was established and patients continued to be treated with Cystagon. On day 1, eligible patients were enrolled and received a randomized assignment to non-morning collection time points for study visits during the Cystagon treatment phase in the first three months.17,57

During the three-month Cystagon treatment phase, patients were treated with their usual dose of Cystagon for three months with no dose adjustments. During the subsequent four months, patients were treated with RP103 every 12 hours, starting at a total daily dose of 70% of their Cystagon dose, with dose increases permitted only during the first month of dosing with RP103 (i.e., at month 3.5 or month 4 visits). During the seven-month treatment phase, study visits occurred monthly during both the three-month Cystagon treatment phase and the four-month RP103 treatment phase, with one additional study visit at month 3.5 to assess WBC cystine levels for potential dose increases during the first month of RP103 treatment. Dose adjustments of RP103 were not permitted during months 5, 6, and 7 of the RP103 phase.57

Patients completing the initial seven-month treatment phase were able to continue to participate in the long-term phase and receive RP103 until it became available through market approval in their region, until treatment duration achieved a maximum of 48 months, or the patient withdrew from the study.57 During the long-term phase of the study, patients were to attend study centre visits on a quarterly basis for the remainder of their participation. During this period, samples were only collected after the morning dose, and central WBC cystine results were unblinded to study investigators for dose adjustments to be made.57

Outcomes

RP103-04

The primary efficacy outcomes measured in this extension period were a WBC cystine concentration measured 30 minutes post-dose at each study visit, and the dose of RP103 which was summarized descriptively and as a proportion of their baseline Cystagon daily dose. These outcomes were obtained at monthly intervals for the first six months and then quarterly.56

Other outcomes reported in the study were quality of life, which was measured via Pediatric Quality of Life Inventory (PedsQL 4.0) (for patients less than 19 years of age) or the Short Form 36 (SF-36) (for patients greater than and equal to 19 years of age), renal function (assessed via estimated glomerular filtration rate [eGFR]), growth (assessed via height Z-scores for age and gender from Centers for Disease Control and Prevention [CDC] growth charts) and swallowing difficulty (assessed via visual analogue scale [VAS]) recorded at study visits.56

RP103-07

The main efficacy outcome for this study was to compare WBC cystine levels at steady state between Cystagon and RP103 after three months of each treatment. The main safety outcome for this study was to examine the adverse events and serious adverse events found to be associated with RP103 treatment.57

To measure WBC cystine control over 24 hours, blood samples were collected twice at each visit: 15 minutes before the morning dose and within 15 minutes before the non-morning dose which was randomized to them. During the first month of RP103 treatment, samples were collected only once per visit, 30 minutes after each morning and evening dose. Investigators were blinded to the central laboratory WBC cystine results during the initial 7-month treatment phase. Dose increases were permitted based on WBC cystine levels during the first month on RP103 only upon written notification by the sponsor medical officer for safety considerations.57

Secondary outcomes were to examine differences in patient quality of life between the use of Cystagon and RP103 via the SF-36 and PedsQL questionnaires, and to evaluate changes in swallowing assessments carried out via VAS. Blood sample measurements were also collected 15 minutes before the dose of Cystagon and 30 minutes after the dose of RP103 at each visit. Pharmacodynamic measurements compared the rate of WBC cystine levels on day 7 of the treatment period for Cystagon and day 7 of the treatment period for RP103.17,57

Patient disposition and exposure

RP103-04

RP103-03 randomized 43 patients, of whom 40 progressed to the extension study up to completion. An additional 20 patients were recruited from two different subgroups: 14 patients less than and equal to 6 years old and six patients who had previous kidney transplant.17 Of the additional 20 patients recruited, one patient in the less than and equal to 6 years old subgroup did not receive at least one dose of RP103, and this patient was therefore not included in the final analysis.17 The median exposure time for all included patients was 3.0 years (1,100 days, range 35 days to 1,677 days). Patient exposure in this study is summarized in Table 16.56

For 19% of patients (11/59), their duration of exposure to RP103 was under 24 months. The majority of patients were in the trial for longer than 24 months (81%, 48/59) and 46% (27/59) stayed in the trial for longer than 36 months. For nine patients, the duration of exposure was greater than 48 months.56

The disposition of patients in this study is summarized in Table 16. As of the interim data cut-off on March 31, 2015, 29 patients were continuing in the study, 25 patients exited the study to transition on to the commercially-available drug (Procysbi), and six patients discontinued from the study for other reasons (three patients discontinued due to adverse effects, one patient withdrew consent, and one patient discontinued due to a physician decision). As a result, a total of 59 patients received the study drug and had pharmacokinetic/pharmacodynamic measurements included for analysis.56

RP103-07

For this trial, 43 patients were screened and signed for consent, after which 41 were enrolled to receive the study drug during the initial three-month Cystagon treatment phase and during the subsequent 4-month RP103 treatment phase. All 41 patients who were enrolled completed two phases of the study, although there was missing data for one of these patients with respect to the primary outcome.57 Based on interim data (collected April 10, 2015), two patients withdrew during the long-term phase, 11 patients completed the study during the long-term phase (remained in the study for at least 24 months), and 28 patients were ongoing in the long-term phase of the study. One patient withdrawal in the long-term phase was elective and the second patient withdrawal was due to a protocol violation.57 Patient disposition is further summarized in Table 17.

Table 13Details of Additional Studies

RP103-04RP103-07
DESIGNS & POPULATIONSStudy DesignPhase III, multi-centre, multi-national, open-label, extensionPhase IIIb, international multi-centre, open-label, uncontrolled study
Locations10 sites in the US, France, NetherlandsUS, Belgium, France, Italy, Netherlands, UK
Number of Participants (N)6041
Inclusion CriteriaPts previously participating in RP103-03 and willing to continue with treatment
OR
Pts with:
  • confirmed diagnosis of nephropathic cystinosis;
  • stable on a Cystagon dose at least 21 days prior to screening;
  • no significant changes in liver function tests and renal function 6 mos before screening;
  • eGFR > 30 mL/min/1.73m2;
  • female pts of childbearing potential who agree to use contraception.
  • Confirmed diagnosis of nephropathic cystinosis
  • On a stable dose of Cystagon at least 21 days prior to screening
  • WBC cystine level > 1 nmol half cystine/mg protein over at least 2 measurements in the 2 yrs prior to screening
  • eGFR > 20 mL/min/1.73m2 and no significant change in renal function within 6 mos before screening
Exclusion CriteriaPts enrolled in RP103-03 who did not complete last scheduled study visit or did not wish to continue treatment with RP103
OR, for pts who did not complete RP103-03:
  • Pts less than 1 year old.
  • Pts with known history currently of the following conditions or other health issues that, in the opinion of the investigator, make it unsafe for participation:
    • inflammatory bowel disease (if currently active) or prior resection of small intestine;
    • heart disease (i.e., myocardial infarction, heart failure, unstable arrhythmias, or poorly controlled hypertension) 90 days prior to screening;
    • active bleeding disorder 90 days prior to screening;
    • malignant disease within last 2 yrs.
  • Pts with hemoglobin level < 10 g/dL at screening or a level that, in the opinion of the investigator, makes it unsafe for participation.
  • Pts with known hypersensitivity to cysteamine or penicillamine.
  • Female pts who are nursing, planning a pregnancy, known or suspected to be pregnant, or have a positive serum pregnancy test.
  • Pts who, in the opinion of the investigator, are unable or unwilling to comply with the protocol.
Pts < 12 yrs of age.
Pts with current history of any of the following conditions:
  • inflammatory bowel disease, or prior resection of the small intestine;
  • heart disease (i.e., myocardial infarction, heart failure, unstable arrhythmias, or poorly controlled hypertension) within 90 days prior to screening;
  • active bleeding disorder within 90 days prior to screening;
  • history of malignant disease within 2 yrs prior to screening.
ObjectiveTo evaluate long-term efficacy, safety, and PK of delayed-release cysteamine bitartrate (after 9-wk initial study, RP103-03)Primary: Compare initial Cystagon phase and subsequent RP103 phase in pts to evaluate control of WBC cystine levels over 24 hours.
Secondary: Assess long-term safety and tolerability of RP103 in pts with cystinosis.
EXPOSUREInterventionLong-term treatment of RP103 q.12.h. starting at a total daily dose of 70% of participants’ total daily Cystagon dose, with opportunity for quarterly dose adjustments.RP103 q.12.h. from mos 3.5, 4, 5, 6, and 7, starting at a total daily dose of 70% of participants’ total daily
Cystagon dose with no dose adjustments Long-term treatment: RP103 q.12.h. with opportunity for quarterly dose adjustments
PhaseIIIIIIb
 Extension Period9 wks + 1 dose up to a minimum of 6 mos (median exposure 3.0 yrs, range of 35 to 1,677 days)Mos 8 to 48, or study termination
 Follow-up6 mos after study completion7 ± 2 days after last study dose or decision to terminate
OUTCOMESMain End Point(s)Mean WBC cystine content
Dose of RP103		WBC cystine over time
Dosing and exposure of RP103
Other End PointsKidney function, somatic growth, BMI, patient QoL (as assessed by PedsQL 4.0)
Harms		Adverse events
NOTESPublicationsClinical study report (RP103-04)35Preliminary report57

BMI = body mass index; eGFR = estimated glomerular filtration rate; mos = months; NA = not applicable; nmol = nanomoles; PK = pharmacokinetics; q.6.h. = every 6 hours; q.12.h. = every 12 hours; PedsQL 4.0 = Pediatric Quality of Life Inventory; PK = pharmacokinetics; pts = patients; QoL = quality of life; WBC = white blood cell; wk = week.

Source: Clinical Study Report;56 Langman et al.;35 Preliminary Study Reports.17,57

Table 14Patient Demographics and Baseline Characteristics – RP103-04

RP103
Number of patients, N60
 Male, n (%)37 (61.7)
 Age at start of treatment (yr), mean (SD)10.9 (6.0)
 RP103-naive (newly enrolled), n (%)19 (32.2)
Previous dose Cystagon, median (mg/m2/day)
 Previously enrolled in RP103-03 (n = 40)1,515.3
 Newly enrolled, ≤ 6 years old (n = 13)983.3
 Newly enrolled, kidney transplant (n = 6)1,092.8
Baseline WBC cystine levels, mean (SD)
 Previously enrolled in RP103-03 (n = 40)0.43 (0.513)
 Newly enrolled, ≤ 6 years old (n = 13)1.41
 Newly enrolled, kidney transplant (n = 6)2.40

mg/m2/day = milligrams/metre squared/day; N = total number of patients in study; n = number of patients in subgroup; SD= standard deviation; yr = year.

Source: Clinical Study Report,56 Langman et al.35

Table 15Summary of Demographics and Baseline Disease Characteristics of RP103-07

All Patients Who Received at Least One Dose
N = 41
Age in years, mean (SD)24.5 (11.56)
Male, n (%)20 (48.8)
White n (%)38 (92.7)
Hispanic2 (4.9)
Black1 (2.0)
Baseline WBC cystine levels, mean nmol half cystine/mg protein (SD)1.403 (1.48)
Baseline eGFR, mean mL/min/1.73m2 (SD)65.4 (29.88)
Mean daily dose Cystagon, mg (SD)1,624 (565.61)

eGFR = estimated glomerular filtration rate; mg = milligram; mL/min/1.73m2 = millilitres/minute/1.73 metres squared; N = total number of patients; n = number of patients in subgroup; nmol = nanomoles; SD = standard deviation; WBC = white blood cell.

Source: Preliminary Study Report57

Table 16Patient Disposition and Treatment Exposure – RP103-04

OverallSubpopulation
RP103-03
(N = 40)		Age ≤ 6 Yrs
(N = 13)		Transplant
(N = 6)
Enrolled in extension study6040146
Received at least 1 dose of RP103, N5940136
Estimated duration of exposure, N (%)
 ≤ 1 yr3 (5.1)2 (5)01 (16.7)
 > 1 yr to ≤ 2 yrs8 (13.6)2 (5)5 (38.5)1 (16.7)
 > 2 yrs to ≤ 3 yrs21 (35.6)15 (37.5)4 (30.8)2 (33.3)
 > 3 yrs to ≤ 4 yrs18 (28.8)12 (27.5)4 (30.8)2 (33.3)
 > 4 yrs to ≤ 5 yrs9 (15.3)9 (22.5)00
Discontinued before end of study, N (%)30 (51)NR
  Participants switched to commercial Procysbi when it became available25 (42)NR
  Physician decision1 (2)NR
  AE3 (5)NR
  Reasons unrelated to AE / wished to withdraw1 (2)NR

AE = adverse event; NR = not reported; yr = year.

Source: Clinical Study Report,56 Langman et al.35

Table 17Patient Disposition in RP103-07

All Patients
(N = 41)		Cystagon Phase
(N = 41)		RP103 Phase
(N = 41)
Screened for Eligibility, N43
Treated On or After Day 1, N41
 Cystagon dosing period41
 RP103 dosing period41
Study Population, N (%)41 (100)41 (100)41 (100)
 Pharmacodynamic41 (100)41 (100)41 (100)
 Per-protocol30 (73.2)30 (73.2)30 (73.2)
 Pharmacokinetics41 (100)41 (100)41 (100)
 Safety41 (100)41 (100)41 (100)
Withdrew Prior to Study Completion, N (%)2 (4.9)
 Withdrawal during either treatment phase0 (0)
 Withdrawal during long-term phase2 (4.9)
Reason for withdrawal
 Non-compliance1 (2.4)
 Patient withdrew consent1 (2.4)

N = total number of patients.

Source: Preliminary Study Report57

Table 18Treatment Exposure in Safety Analysis Set in RP103-07

ParameterCystagon Phase
(N = 41)		RP103 Phase
(N = 41)		Long-Term Phase
(N = 41)
Duration of study drug exposure, mean days (SD)91 (5.64)117.7 (8.24)167.0 (153.08)
Duration of study drug exposure, median days (range)91 (82,108)119.0 (98,137)168.0 (1, 511)
Days with a missed dose, mean days (SD)10.9 (17.59)11.9 (17.52)26.2 (64.48)
Ratio of days with a missed dose to duration of exposure, mean (SD)0.1 (0.18)0.1 (0.15)0.1 (0.21)
Comparison of ratios between Cystagon vs. RP103, P values0.6857

SD = standard deviation.

Source: Preliminary Study Report.57

Efficacy

RP103-04

Long-term efficacy was summarized for each parameter based on patients who remained in the study during the open-label period and who had data at the reported collection time points. Patients were stratified by subgroup (previous patients in RP103-03; patients less than and equal to 6 years of age; post-renal transplant patients). Overall, WBC cystine levels were able to stay below 1 nmol half cystine/mg protein for patients extending therapy, and were able to decrease steadily for newly enrolled patients over the length of the study (mean [SD] of 0.54 [0.393] at approximately 3.75 years).6,17 Additionally, the total daily dose of RP103 at month 1 was 82% of the previous Cystagon total daily dose and the RP103 dose level was generally maintained over the duration of the study, indicating that the long-term administration of RP103 did not require an increase in the daily dose requirement over time.6 For newly enrolled patients less than and equal to 6 years of age (n = 13), the initial starting dose was 70% of the Cystagon dose at time of entry to study. The mean dose for this subpopulation was generally stable over time. For newly enrolled patients who had previous renal transplantation, the initial dose (70% of the Cystagon dose at time of entry) and mean RP103 dose level increased somewhat over time at later visits throughout the study. These efficacy outcomes also improved throughout the long-term trial period and are summarized in Table 19.6,17

In regard to secondary outcomes, renal function was preserved throughout the study time period, with no significant differences with respect to eGFR, with respect to patients less than and equal to 6 years of age as well as patients who were transplant recipients. In regard to height z score, a growth retardation was found in patients at baseline (–1.54) which is to be expected as part of disease pathogenesis. Due to maintenance of WBC cystine levels below a target of less than 1 nmol half cystine/mg protein, this growth trajectory was sustained throughout treatment. A VAS, which was used to assess pain-associated swallowing difficulty, was measured on a 0 to 10 metric. It was reported that the mean changes from baseline in this metric were generally small over the course of this study and no distinct trends were reported. Lastly, quality of life was assessed with either the PedsQL 4.0 for patients less than 19 years of age), or the Short Form 36 (SF-36) for patients greater than and equal to 19 years of age instrument. For the PedsQL 4.0, the mean per cent change showed an improvement in functionality relative to the baseline scores documented in RP103-03 in all five categories (Physical, Emotional, Social, School and Total) at the first visit in month 1 of RP103-04, and this improvement was maintained from baseline across the four-year duration of the study. Secondary efficacy outcomes are summarized in Table 20.6,17

RP103-07

For both Cystagon and RP103 treatment phases, WBC cystine levels remained within a relatively narrow range for the majority of patients. Preliminary results are fully summarized in Table 21. The average WBC cystine value was found to be closer to the less than 1 nmol half cystine/mg protein target in patients during the Cystagon treatment phase of the study than in the RP103-treatment phase of the study.57 During the Cystagon phase, non-morning WBC cystine was on average 0.213 nmol half cystine/mg protein lower than the corresponding morning WBC cystine level during the RP103 phase.57 In the per-protocol population, the variability in WBC cystine levels between the morning and non-morning samples was found to be significantly lower in patients during their treatment with RP103 than during treatment with Cystagon (P = 0.0081).57

Dosing compliance, which was measured by the number of days with one or more missed doses, was similar during the Cystagon and RP103 phases. The mean average daily dose during the three-month Cystagon phase was 1,624 mg. The mean average daily dose during the subsequent three-month RP103 phase was 1,168 mg (72% of the mean dose during the Cystagon phase). The median duration of RP103 exposure during the long-term phase as of the interim data cut-off date of 10 April 2015 was 168 days.17,57

Table 19RP103-04 Extension Main Efficacy Outcomes Over Time

VisitApproximate Yrs in StudySubgroups
WBC Cystine (nmol half cystine/mg protein)
RP103-03 (N = 40)
Mean (SD), [n]		Age ≤ 6 Yrs (N = 13)
Mean (SD), [n]		Transplant (N = 6)
Mean (SD), [n]
Baselinea0 to 0.1 yr0.43 (0.513)
[n = 39]		1.41 (1.030)
[n = 13]		2.40 (1.687)
[n = 5]
Monthly visit 60.5 yr0.46 (0.431)
[n = 38]		2.00 (1.729)
[n = 13]		1.75 (1.242)
[n = 5]
Quarterly visit 21.0 yr0.42 (0.352)
[n = 38]		1.10 (0.578)
[n = 12]		1.28 (0.830)
[n = 5]
Quarterly visit 41.5 yrs0.49 (0.344)
[n = 37]		1.31 (1.480)
[n = 11]		1.57 (0.944)
[n = 4]
Quarterly visit 62.0 yrs0.52 (0.304)
[n = 35]		1.40 (2.188)
[n = 6]		0.62 (0.368)
[n = 3]
Quarterly visit 82.5 yrs0.44 (0.371)
[n = 29]		0.98 (0.487)
[n = 6]		0.84 (0.550)
[n = 3]
Quarterly visit 103.0 yrs0.39 (0.290)
[n = 20]		0.90 (0.386)
[n = 3]		1.69 (0.682)
[n = 3]
Quarterly visit 133.75 yrs0.54 (0.393)
[n = 19]		NANA
Mean RP103 Dose (mg/m2/day) Over Time
RP103-03 (N = 40)
Mean (SD), [n]		Age ≤ 6 Yrs (N = 13)
Mean (SD), [n]		Transplant (N = 6)
Mean (SD), [n]
Baselinea0 to 0.1 yr1,275.99 (242.663)
[n = 39]		813 (251.494)
[n = 13]		868.52 (273.369)
[n = 5]
Monthly visit 60.5 yr1,258.08 (299.656)
[n = 38]		914.46 (286.071)
[n = 13]		783.41 (320.949)
[n = 5]
Quarterly visit 21.0 yr1,232.76 (344.772)
[n = 38]		910.60 (285.206)
[n = 12]		911.90 (330.893)
[n = 5]
Quarterly visit 41.5 yrs1,224.76 (350.318)
[n = 36]		938.04 (252.093)
[n = 11]		792.49 (276.809)
[n = 4]
Quarterly visit 62.0 yrs1,196.78 (350.307)
[n = 35]		932.63 (244.550)
[n = 6]		1,109.35 (333.238)
[n = 3]
Quarterly visit 82.5 yrs1,116.18 (349.867)
[n = 29]		829.93 (213.787)
[n = 6]		1,086.34 (313.558)
[n = 3]
Quarterly visit 103.0 yrs1,079.56 (225.781)
[n = 29]		765.75 (240.093)
[n = 3]		1,091.81 (335.229)
[n = 3]
Quarterly visit 133.75 yrs996.24 (274.637)
[n = 17]		NRNR
a

Baseline refers to measurements or means taken from the first available visit in month 1 for patients from RP103-03 and day 1 for the other two subpopulations. For day 1, the WBC cystine value immediately prior to the RP103 dose was summarized.

N = total number of patients; n = number of patients in subgroup; NR = not reported; nmol = nanomoles; SD = standard deviation; yr = year.

Source: RP103-04 Clinical Study Report.56

Table 20RP103-04 Extension Efficacy Outcomes – Individual Parameters

VisitApproximate Years in StudySubgroups
Renal Function (eGFR)
RP103-03 (N = 40)
Mean (SD), [n]		Age ≤ 6 Yrs (N = 13)
Mean (SD), [n]		Transplant (N = 6)
Mean (SD), [n]
Baselinea0 to 0.1 yr66.04 (26.326)
[n = 38]		74.13 (26.131)
[n = 13]		71.68 (24.374)
[n = 6]
Monthly visit 60.5 yr61.23 (24.861)
[n = 38]		73.01 (26.896)
[n = 13]		53.89 (18.907)
[n = 5]
Quarterly visit 21.0 yr58.31 (22.479)
[n = 38]		67.87 (24.759)
[n = 13]		55.70 (17.967)
[n = 5]
Quarterly visit 41.5 yrs58.80 (23.650)
[n = 38]		72.37 (24.831)
[n = 13]		57.79 (25.587)
[n = 5]
Quarterly visit 62.0 yrs56.11 (24.576)
[n = 35]		77.08 (25.918)
[n = 6]		70.02 (30.519)
[n = 3]
Quarterly visit 82.5 yrs59.17 (26.789)
[n = 29]		71.27 (23.826)
[n = 6]		76.21 (36.561)
[n = 3]
Quarterly visit 103.0 yrs60.87 (26.602)
[n = 21]		65.69 (15.203)
[n = 4]		75.73 (36.174)
[n = 3]
Quarterly visit 133.75 yrs57.24 (25.012)
[n = 20]		NANA
Height z Score for Age and Gender in Patients ≤ 12 Yrs
(N = 38)
Mean (SD) [n]
Baselinea0 to 0.1 yr−1.54 (1.016)
[n = 38]
Monthly visit 60.5 yr−1.45 (1.037)
[n = 37]
Quarterly visit 21.0 yr−1.51 (1.083)
[n = 37]
Quarterly visit 41.5 yrs−1.60 (1.063)
[n = 37]
Quarterly visit 62.0 yrs−1.73 (0.987)
[n = 30]
Quarterly visit 82.5 yrs−1.77 (1.197)
[n = 24]
Quarterly visit 103.0 yrs−1.71 (0.782)
[n = 16]
Quarterly visit 133.75 yrs−1.80 (0.995)
[n = 11]
a

Baseline refers to measurements or means taken immediately prior to enrolment into RP103-04. All time points do not refer to time after initiation of RP103 treatment, but to time in the extension period.

eGFR = estimated glomerular filtration rate; N = total number of patients; n = number of patients in subgroup; SD = standard deviation; yr = year.

Source: Clinical Study Report.56

Table 21Primary Outcomes and Associated Individual Parameters in RP103-07 Trial Assessed in Pharmacodynamic Population

ParameterCystagon Treatment PhaseRP103 Treatment PhaseOne–Sample t-Test Two-Sided P ValuePaired t-Test Two-Sided P Value
N = 41N = 40
WBC cystine level, nmol half cystine/mg protein
 Mean morning value at end of treatment phase (SD)1.068 (1.3162)1.467 (1.7972)
 Mean evening value at end of treatment phase (SD)1.160 (1.6296)1.473 (1.6460)
Difference in morning and non-morning WBC cystine values
 Mean difference between morning and non-morning WBC cystine values (SD)−0.213 (0.5490)0.033 (0.5513)0.01860.7047
 Mean difference between morning and non-morning log WBC cystine values (SD)−0.200 (0.4850)0.087 (0.3981)0.0081
 Mean difference between morning and non-morning log WBC cystine values, per-protocol population (SD)−0.101
(N = 30)		0.171
(N = 30)		0.0167
Daily dose over treatment phases, mean (SD)1,624 (565.61)1,168 (473.84)
Concurrent use of gastric acid-reducing medication
 At least 1 gastric acid-reducing concomitant medication (SD)21 (51.2)21 (51.2)
 Days of usage of gastric acid-reducing concomitant medication, mean (SD)91.24 (7.520)90.71 (37.140)
Estimated Glomerular Filtration Rate, mL/min/1.73m2
 Mean value at end of treatment phase (SD)64.3 (28.32)62.6 (30.51)
 Change from baseline at end of treatment phase (SD)−1.0 (10.08)−2.6 (10.39)

mL/min/1.73m2= milligram/minute/1.73 metres squared; N = total number of patients; nmol= nanomoles; SD = standard deviation; WBC = white blood cell.

Source: Clinical Study Report.35

Harms

RP103-04

Total reported adverse events in RP103-04 are summarized in Table 22. Of the 59 patients participating in the RP103-04 extension, all but two patients (97%) experienced at least one treatment-emergent adverse event (TEAE). The most commonly reported adverse events included: vomiting (66.6%); headache (30.5%); diarrhea (22%); nausea (22%); influenza (20%); gastroenteritis, abdominal pain, upper respiratory tract infection (16.9% each). There were no deaths during the study. Three patients who were previously enrolled in RP103-03 experienced at least one TEAE which led to discontinuation from the study. These included one 14-year-old female who discontinued due to Grade 2 vomiting, a seven-year-old male who discontinued due to Grade 1 dyspepsia and Grade 1 decreased appetite, and a 15-year-old male who discontinued due to Grade 3 renal failure.56

RP103-07

The harms reported in this study are summarized in Table 22. In comparing the initial Cystagon and RP103 treatment phases, there was a higher incidence of mild to moderate gastrointestinal adverse events during the RP103 treatment phases. Four patients reported at least one TEAE related to study drug in the Cystagon treatment phase, compared with 19 patients in the RP103 treatment phase, No patients discontinued treatment due to an adverse event.57

There were eight serious TEAEs that occurred during the Cystagon phase, one of which was assessed to possibly be related to Cystagon treatment. There was no dosage adjustment made to treatment, and the adverse event was reported to have resolved. There were 12 serious TEAEs which occurred during the RP103 phase, two of which were considered to possibly be associated with RP103 treatment. One of these events was a case of diarrhea and another was a case of abdominal pain, both of which did not result in a dosage change and both of which were reported to be resolved or recovered at a later date. Six patients were reported to have serious TEAEs occurring in the long-term phase. All these incidences were reported to be unlikely related or unrelated to RP103 treatment and all had an outcome of resolved, either with or without sequelae.57

Table 22Harms Within Safety Population of Additional Studies

RP103-04RP103-07
OverallContinued from RP103-03Age ≤ 6 YrsTransplantedCystagon PhaseRP103 PhaseLong-Term Phase
N = 59N = 40N = 13N = 6N = 40N = 41N = 41
Pts with TEAE, N (%)57 (96.6)40 (100)13 (100)4 (66.7)31 (75.61)37 (90.24)23 (56.10)
Pts with Serious TEAE, N (%)29 (49.2)21 (52.5)7 (53.8)1 (16.7)5 (12.20)7 (17.07)6 (14.63)
Pts with drug-related TEAE, N (%)35 (59.3)28 (70.0)5 (38.5)2 (33.3)4 (9.76)19 (46.34)5 (12.20)
Pts with TEAE leading to withdrawal, N (%)3 (5.1)3 (7.5)00000
Pts with Grade 3 (Severe) TEAE, N (%)21 (35.6)14 (35.0)5 (38.5)2 (33.3)

N = total number of patients; pts = patients; TEAE= treatment-emergent adverse event; yrs = years.

Source: Clinical Study Report,56 Langman et al.;16 Preliminary Study Reports17,57

Limitations

RP103-04

The main limitation associated with this study was that it included a select population which elected to continue treatment with RP103. As a result, this extension study risks compromising a population of patients who would be more likely to respond to and tolerate RP103, thus decreasing the generalizability to all patients who may benefit from this treatment.

In the trial summarized above, it is difficult to identify whether there is a cause-and-effect relationship between RP103 and its reported efficacy and safety outcomes, as it was not a controlled trial. Furthermore, due to the open-label trial design, in which both the investigators and the patients were unblinded to treatment allocation, it is difficult to determine whether the reporting of adverse events by patients or the assessment of adverse events by investigators could have been influenced. Finally, smaller sample sizes make statistical calculations difficult and limit the interpretability of results.

RP103-07

This was an open-label, crossover, single-arm design study which sought to test superiority of intra-patient variance in WBC cystine levels through 24 hours, as well as to follow long-term outcomes for efficacy, safety, and pharmacokinetics of the twice-daily regimen of RP103. Due to the crossover design of the study between active therapies, there is a risk of bias favouring RP103 due to carryover effects from Cystagon therapy. Although the half-life of Cystagon is known to be six hours, it is difficult to rule out that any clinical changes seen in this study may be due to the patient initially being on stable Cystagon therapy. Therefore, in the period of time in which this drug was studied, effects observed after the crossover period risk being falsely attributed to RP103. This issue is compounded by the fact that this study is uncontrolled, increasing difficulty in assessing the true clinical effect of RP103. If there happens to be no change in parameters after the crossover period, it is more difficult to distinguish between treatment effect and no effect at all.

Furthermore, this study found a significantly lower within-patient difference between morning and non-morning WBC cystine levels when patients were treated with RP103, which is not known to be a clinically relevant outcome. While it is established that maintaining a target WBC cystine less than and equal to 1 nmol half cystine/mg protein is associated with a delay in long-term disease progression,1,3,13,50 it is not known whether reducing the variance of this value will pose any discernable benefit to patients with nephropathic cystinosis. In fact, patients in this study had a higher average WBC cystine value while using RP103 than they did using Cystagon (1.467 versus 1.068 nmol half cystine/mg protein), which is known to be associated with worse long-term outcomes in this patient population. With regard to relevant clinical outcomes such as renal function and height scores, the results were difficult to interpret due the dropout rate over time. Finally, the lack of blinding in this study may have impacted the reporting of adverse events which were reported with regard to frequency and magnitude.

Additional limitations of this study include: an unclear history of nephropathic cystinosis in this patient population, and small patient numbers. Finally, quality of life questionnaires and swallowing assessments were reported to be recorded outcomes in this study, but the results of these were not provided in the preliminary document.57

Summary

RP103-04

The objective of this long-term study was to acquire data on the efficacy, safety, and tolerability of RP103 administered every 12 hours to patients with nephropathic cystinosis over a course of two years and greater. After the pivotal study, the study population was extended to include patients less than seven years of age and patients who had previously undergone a renal transplant. It was demonstrated that the long-term use of RP103 was associated with WBC cystine levels that remained within the desired target of less than and equal to 1 nmol half cystine/mg protein. However, the majority of patients (97%) experienced adverse events. Commonly reported adverse events were: vomiting, diarrhea, headache, and nausea. It was hypothesized by investigators that the adverse events experienced by patients may be related to the clinical disease; however medication involvement cannot be ruled out. Limitations of this study were its open-label and single-arm design, without a control group.

RP103-07

Results from this phase IIIb international, multi-centre, open-label, uncontrolled, long-term efficacy, safety and pharmacokinetic trial suggest that RP103 has reduced variability of WBC cystine (as measured by mean within-patient difference between morning and evening WBC cystine level) during RP103 treatment compared with Cystagon treatment. However, the absolute values of WBC cystine were lower during the Cystagon treatment phase, which was more closely in line with a target clinical value of less than and equal to 1 nmol half cystine/mg protein in patients with nephropathic cystinosis.

In this trial, the majority of patients (90.2%) experienced adverse events during the RP103 phase of the study. Commonly reported adverse events occurring in this trial were: diarrhea, vomiting, abdominal pain, and nausea. No deaths occurred during the trial, although it was noted that there was a death of a patient that occurred subsequent to study completion, due to trauma.

It is of note that the long-term outcomes in this trial still offer limited interpretability due to the uncontrolled, unblinded nature of the study.

Copyright © 2018 Canadian Agency for Drugs and Technologies in Health.

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Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/

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