E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Enteric or primary hyperoxaluria and hyperoxalemia |
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E.1.1.1 | Medical condition in easily understood language |
Enteric or primary hyperoxaluria and hyperoxalemia, meaning that there is a large amount of oxalate in urine (hyperoxaluria) and blood (hyperoxalemia). |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Evaluate the efficacy of ALLN-177 in reducing plasma and urine oxalate (UOx) levels in subjects with enteric or primary hyperoxaluria and hyperoxalemia Evaluate safety of ALLN-177 in subjects with enteric or primary hyperoxaluria and hyperoxalemia Exploratory evaluation of oxalate decarboxylase physiology in subjects with enteric or primary hyperoxaluria and hyperoxalemia |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed and dated the Institutional Review Board (IRB)/Ethics Committee (EC) approved informed consent form (ICF) or Assent before undergoing any Screening 2. Aged 12 or older with body weight ≥35kg 3. Has diagnosis of primary hyperoxaluria determined by standard diagnostic methods, or a history of enteric hyperoxaluria (urinary oxalate excretion ≥ 40 mg/24h [ ≥ 0.45 mmol/24h] normalized for body surface area in children, that is associated with a known underlying enteric disorder associated with malabsorption such as bariatric surgery, Crohn’s disease, short bowel syndrome, or other malabsorption syndrome) - Note: Subjects with estimated glomerular filtration rate (eGFR) >15 mL/min/1.73m2 who have suspected enteric hyperoxaluria but no elevated 24-hour UOx should obtain a pre-screening 24-hour urine collection to determine UOx level prior to undergoing full screening procedures after providing appropriate consent - Note: Subjects with enteric hyperoxaluria on dialysis or with eGFR ≤15 mL/min/1.73m2 must have an elevated UOx level documented in the medical record. - Note: 24-hour urine collections are not obtained in subjects on dialysis 4. In subjects with eGFR >15 mL/ min/1.73m2, UOx at Screening ≥ 40 mg/24h ( ≥ 0.45 mmol/24h; normalized to body surface area in children) on an adequate collection (i.e., appropriate ratio of creatinine [mg]/body weight [kg] for gender) - Note: 24-hour urine collections are not obtained in subjects with eGFR ≤15 mL/min/1.73m2 or on dialysis - Note: A pre-screen 24-hour UOx obtained within 6 weeks prior to Screening can be used to satisfy this screening UOx entry criterion 5. In subjects with enteric hyperoxaluria, has estimated glomerular filtration rate (eGFR) <45 mL/ min/1.73m2 at Screening, or has been on dialysis for greater than 3 months but less than 2 years. The number of subjects with eGFR <15 mL/ min/1.73m2 or on dialysis will be limited to 25% of total enrollment 6. In subjects with enteric hyperoxaluria, documented history of elevated plasma oxalate (>5 μmol/L) - Note: Subjects with no documented elevated plasma oxalate who are interested in participating in this study should undergo a pre-screening plasma oxalate test prior to undergoing full screening procedures to determine whether they have elevated plasma oxalate, after providing appropriate consent. For subjects on hemodialysis, the plasma samples will be obtained immediately prior to dialysis, optimally following the longer interval between dialysis treatments. 7. In subjects with enteric hyperoxaluria, plasma oxalate >5 μmol/L at screening - Note: A plasma oxalate obtained within 6 weeks prior to Screening can be used to satisfy this entry criterion 8. For subjects taking concomitant medication for management of kidney stone risk factors (e.g., pyridoxine, thiazides, citrate supplements, allopurinol): has been on a stable dose regimen for >8 weeks prior to Screening, with no changes in dosing (dose level or dosing frequency) anticipated during the remainder of the study 9. For female subjects: Is either medically incapable of pregnancy (e.g., has undergone hysterectomy or tubal ligation or has experienced prolonged [≥ 1 year prior to Screening] amenorrhea) or, if a woman of childbearing potential, has a negative Screening serum pregnancy test, is not pregnant or nursing at Screening, and agrees to use an effective (approved by the Investigator) method of birth control for the duration of the study 10. Subjects on dialysis, must be stable on dialysis for greater than 3 months. |
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E.4 | Principal exclusion criteria |
1. Is unable or unwilling to discontinue Vitamin C supplementation at Screening and for the duration of the study 2. Any clinically significant findings during Screening, any ongoing clinically significant illness requiring changes in management within 1 month prior to or during Screening (e.g., flare of inflammatory bowel disease), or initiation of dialysis or any surgical/invasive procedure is planned during the study 3. Malignancy or treatment for malignancy within 12 months prior to screening with the exception of localized basal cell or squamous cell skin cancer. - Note: Subjects in remission on stable doses of chronic suppressive or maintenance therapies are not excluded 4. Has active autoimmune disorder or other condition requiring therapy with high doses of systemic steroids (i.e., >10 mg/day prednisone or equivalent) or intensification of other immunosuppressant therapy within 1month prior to or during Screening - Note: Subjects on stable chronic or maintenance doses of steroids or other immunosuppressant drugs, including transplant recipients, are not excluded 5. Has participated in any other ALLN-177 clinical study, or participation in another drug or device clinical trial within 30 days prior to or during Screening 6. Is not, per Investigator judgment, an ideal clinical trial candidate due to a personal issue (e.g., unwillingness/inability to comply with protocol) or medical condition (e.g., mental illness, laboratory abnormalities) that is likely to impede successful study completion |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy: - Change in plasma oxalate - Change in 24-hr UOx excretion - Proportion of subjects with reduction in plasma oxalate by ≥20% and/or to <5 μmol/L - Proportion of subjects with reduction in 24-hr UOx excretion ≥20% and/or to <40 mg/24 h Safety: - Incidence of treatment-emergent adverse events (TEAEs) that include clinically significant adverse changes in clinical laboratory values, vital signs and physical examination. - Passage of kidney stones, procedures, hospitalizations, or Emergency Room visits related to kidney stones will be considered AEs of special interest Exploratory: - Blood formate and oxalate decarboxylase levels |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy will be assessed based on change from baseline in plasma oxalate and/or 24-hr urine oxalate excretion while on treatment with ALLN-177. Note: Subjects on dialysis or with eGFR <15 mL/ min/1.73m2 will be excluded from analysis of 24-hr urine oxalate excretion. Treatment-emergent adverse events (TEAEs), changes in clinical laboratory values, vital signs and physical examination will be presented descriptively, overall and by type of hyperoxaluria, age group and level of CKD at baseline, as appropriate. Blood formate and oxalate decarboxylase results will be displayed for each time point when obtained, and mean and percent change from fasting to post-prandial/post-dose will be calculated at the relevant time points. |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Germany |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |