Cystinosis
Conditions
Keywords
cystinosis, cysteamine, inheritable disease, orphan disease, CTNS protein, human, metabolic disease, nephropathic cystinosis
Brief summary
Cystinosis is an inherited disease that if untreated, results in kidney failure as early as the first decade of life. The current marketed therapy is Cystagon® (cysteamine bitartrate) which must be taken every six hours for the rest of the patient's life to prevent complications of cystinosis. RP103 is a formulation of cysteamine bitartrate that is being studied to see if it may be able to be given less frequently, once every 12 hours, and have similar results to four times a day Cystagon®.
Detailed description
This is a multi-center, open-label, randomized, cross-over study to determine whether steady-state, twice a day treatment with Cysteamine Bitartrate Delayed-release Capsules(RP103) results in comparable depletion of white blood cell (WBC) cystine levels compared to the existing four times a day cysteamine treatment. It will involve up to 20 clinic visits plus intermittent home use of the RP103. Most of these clinic visits occur in clusters of 3-4 consecutive days. Eligible patients will be offered enrollment into a long-term follow up study. Study with completed results acquired from Horizon in 2024.
Interventions
DRUGCystagon® (Cysteamine Bitartrate)
Run-in Period (Weeks 1, 2, 3) and Period 1 (Weeks 4, 5, 6) or Period 2 (Weeks 7, 8, 9); Immediate crossover to opposite treatment than taken during Period 1: Every 6H, supplied in 150 and 50mg capsules/Duration of Treatment: 3 weeks each period used
DRUGCysteamine Bitartrate Delayed-release Capsules (RP103)
Period 1 (Weeks 4, 5, 6) or Period 2 (Weeks 7, 8, 9); Immediate crossover to opposite treatment than taken during Period 1: Every 12H, supplied in 75 and 25mg capsules/Duration of Treatment: 3 weeks
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female subjects must have nephropathic cystinosis. * Subjects must be on a stable dose of Cystagon® sufficient to maintain their white blood cell (WBC) cystine level at ≤ 1.0 nmol/half-cystine/mg protein. * Subjects must be able to swallow their typically administered Cystagon® capsule with the capsule intact. * Within the last 6 months, no clinically significant change in liver function \[i.e., ALT, AST, total bilirubin\] and renal function \[i.e., estimated GFR\] at Screening as determined by the Investigator. * Subjects with an estimated GFR (corrected for body surface area) \> 30 mL/min/1.73m2. * Sexually active female subjects of childbearing potential (i.e., not surgically sterile \[tubal ligation, hysterectomy, or bilateral oophorectomy\] or at least 2 years naturally postmenopausal) must agree to utilize the same acceptable form of contraception from Screening through completion of the study. * Subjects must be willing and able to comply with the study restrictions and requirements. * Subjects or their or their parent or guardian must provide written informed consent and assent (where applicable) prior to participation in the study.
Exclusion criteria
* Subject's age \< 6 years old or subject's weight \< 21 kg. * Subjects with a known history, currently of the following conditions or other health issues that make it, in the opinion of the investigator, unsafe for them to participate: inflammatory bowel disease (if currently active) or have had prior resection of small intestine; Heart disease (e.g., myocardial infarction, heart failure, arrhythmias or poorly controlled hypertension) 90 days prior to Screening; Active bleeding disorder 90 days prior to Screening; Malignant disease within the last 2 years. * Patients with a hemoglobin level \< 10 g/dL at Screening or a level that, in the opinion of the investigator, makes it unsafe for the subject to participate. * Subjects receiving any form of cysteamine medication through a gastric tube. * Subjects who are receiving maintenance dialysis or who have had a kidney transplant. * Subjects who are on an active kidney transplant list or who are planning to receive a kidney transplant within 3 months of Screening. * Subjects with known hypersensitivity to cysteamine or penicillamine. * Female subjects who are nursing, planning a pregnancy, known or suspected to be pregnant, or have a positive serum pregnancy screen. * Subjects who have a made a blood donation within 30 days of Screening. * Subjects who, in the opinion of the Investigator, are not able or willing to comply with the protocol.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The Steady-state White Blood Cell Cystine Levels of RP103 Compared to Cystagon® | 4 weeks after the last subject has completed the study |
Secondary
| Measure | Time frame |
|---|---|
| Comparison of Cysteamine PK Profiles, Steady State Cmax, Between RP103 and Cystagon®. | 4 weeks after the last subject has completed the study |
| Comparison of Cysteamine PK Profiles, Steady State Tmax, Between RP103 and Cystagon®. | 4 weeks after the last subject has completed the study |
| Comparison of Cysteamine PK Profiles, AUC(0-t), Between RP103 and Cystagon®. | 6 hours post dosing for Cystagon®; 12 hours post dosing for RP103. |
Countries
France, Netherlands, United States
Participant flow
Pre-assignment details
Participants randomized to each per sequence Arm are expected to remain in the same Arm throughout all intervention periods.
Participants by arm
| Arm | Count |
|---|---|
| RP103 and Cystagon® Crossover Per Protocol Population | 39 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (3 Weeks) | Infection after pre-planned surgery | 0 | 1 |
| First Intervention (3 Weeks) | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | RP103 and Cystagon® Crossover |
|---|---|
| Age, Categorical <=18 years | 36 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Age, Continuous | 11.9 years STANDARD_DEVIATION 4.33 |
| Region of Enrollment France | 13 participants |
| Region of Enrollment Netherlands | 4 participants |
| Region of Enrollment United States | 22 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 43 | 5 / 41 |
| serious Total, serious adverse events | 6 / 43 | 1 / 41 |
Outcome results
Primary
The Steady-state White Blood Cell Cystine Levels of RP103 Compared to Cystagon®
Time frame: 4 weeks after the last subject has completed the study
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RP103 | The Steady-state White Blood Cell Cystine Levels of RP103 Compared to Cystagon® | 0.5152 nmol ½ Cystine / mg protein | Standard Error 0.05555 |
| Cystagon® | The Steady-state White Blood Cell Cystine Levels of RP103 Compared to Cystagon® | 0.4367 nmol ½ Cystine / mg protein | Standard Error 0.05555 |
Comparison: 16-subject study will have 90% power to reject the null hypothesis of non-inferiority at the 0.025 level of significance with a non-inferiority margin of 0.3. Final analysis was performed at a nominal significance level of 0.02104.p-value: 0.000195.8% CI: [0.0107, 0.1464]t-test, 1 sided
Secondary
Comparison of Cysteamine PK Profiles, AUC(0-t), Between RP103 and Cystagon®.
Time frame: 6 hours post dosing for Cystagon®; 12 hours post dosing for RP103.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RP103 | Comparison of Cysteamine PK Profiles, AUC(0-t), Between RP103 and Cystagon®. | 357 AUC(0-t) (min*mg/L) | Standard Deviation 150 |
| Cystagon® | Comparison of Cysteamine PK Profiles, AUC(0-t), Between RP103 and Cystagon®. | 739 AUC(0-t) (min*mg/L) | Standard Deviation 334 |
95% CI: [1.75, 2.39]
Secondary
Comparison of Cysteamine PK Profiles, Steady State Cmax, Between RP103 and Cystagon®.
Time frame: 4 weeks after the last subject has completed the study
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RP103 | Comparison of Cysteamine PK Profiles, Steady State Cmax, Between RP103 and Cystagon®. | 2.73 Cmax (mg/L) | Standard Deviation 1.36 |
| Cystagon® | Comparison of Cysteamine PK Profiles, Steady State Cmax, Between RP103 and Cystagon®. | 3.70 Cmax (mg/L) | Standard Deviation 1.72 |
95% CI: [1.17, 1.67]
Secondary
Comparison of Cysteamine PK Profiles, Steady State Tmax, Between RP103 and Cystagon®.
Time frame: 4 weeks after the last subject has completed the study
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RP103 | Comparison of Cysteamine PK Profiles, Steady State Tmax, Between RP103 and Cystagon®. | 72 Tmax (minute) | Standard Deviation 31 |
| Cystagon® | Comparison of Cysteamine PK Profiles, Steady State Tmax, Between RP103 and Cystagon®. | 187 Tmax (minute) | Standard Deviation 89 |
95% CI: [90, 150]