E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
Primary hyperoxaluria is where the liver overproduces oxalate. As a result calcium-oxalate crystals form in the urinary system and lead to the formation of kidney stones and impaired kidney function. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020703 |
E.1.2 | Term | Hyperoxaluria |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
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 |
To assess the efficacy of DCR PHXC in reducing urinary oxalate burden in patients with PH (types 1 and 2) |
|
E.2.2 | Secondary objectives of the trial |
Key Secondary: To assess the efficacy of DCR PHXC in reducing urinary
oxalate burden over time in patients with PH
Secondary:
1. To evaluate the effect of DCR PHXC on stone burden in patients with
PH
2. To evaluate the effect of DCR-PHXC on plasma oxalate in patients with
PH
3. To evaluate the effect of DCR PHXC on eGFR
4. To assess the safety of DCR PHXC in patients with PH
5. To characterize the PK of DCR PHXC in patients with PH |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In order to be eligible to participate in this study, an individual must
meet all of the following criteria:
Age
1. At least 6 years of age, at the time of signing the informed
consent/assent.
Type of Participant and Disease Characteristics
2. Documented diagnosis of PH1 or PH2, confirmed by genotyping
(historically available genotype information is acceptable for study
eligibility)
3. 24-hour Uox excretion ≥ 0.7 mmol (adjusted per 1.73 m2 BSA in
participants < 18 years of age) in both collections performed in the
screening period. Of the first 24 participants enrolled, at least 12 (50%)
must have at least one 24 hour Uox excretion ≥ 1.6 mmol (adjusted per 1.73 m2 BSA in participants aged < 18 years).
4. Less than 20% variation between the two 24-hour urinary creatinine
measurements in the screening period. Individuals who do not achieve <
20% variation between the 2 screening values may undergo a second
round of urine collection. An extra 7 calendar days may be added to the
screening window for participants to complete a second round of urine
collection. Should potential participants again fail to achieve the within-
20% variation, they will be excluded from participation.
5. Estimated GFR at screening ≥ 30 mL/min normalized to 1.73 m2 BSA,calculated using the CKD-EPI equation in participants aged ≥ 18 years(Levey & Stevens, 2010) or the2012 multivariate equation by Schwartz in participants aged 6 to 17 years (Schwartz et al., 2012).
In Japan, the equation by Matsuo et al. will be used for participants aged ≥ 18 years (Uemura et al., 2014 Matsuo et al., 2009).
Sex
6. Male or female
Male participants:
A male participant with a female partner of childbearing potential must
agree to use contraception, as detailed in Section 10.4.2, during the
treatment period and for at least 12 weeks after the last dose of study
intervention and refrain from donating sperm during this period.
Female participants:
A female participant is eligible to participate if she is not pregnant (see
Section 10.4.1), not breastfeeding, and at least 1 of the following
conditions applies:
Not a woman of childbearing potential (WOCBP) as defined in Section
10.4.1
OR
A WOCBP who agrees to follow the contraceptive guidance in Section
10.4.2 during the treatment period and for at least 12 weeks after the
last dose of study intervention.
Contraceptive use by men or women should be consistent with local
regulations regarding the methods of contraception for those
participating in clinical studies.
Informed Consent/Assent
7. Participant (and/or participant's parent or legal guardian if
participant is a minor [defined as patient < 18 years of age, or younger
than the age of majority, according to local regulations]) is capable of
giving signed informed consent, which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF)
and in this protocol.
a. Adolescents (12 to < 18 years of age, or older than 12 years but
younger than the age of majority, according to local regulations) must
be able to provide written assent for participation.
b. For children younger than 12 years of age, assent will be based on
local regulations. |
|
E.4 | Principal exclusion criteria |
An individual who meets any of the following criteria will be excluded
from participation in this study:
Medical Conditions
1. Prior renal or hepatic transplantation; or planned transplantation
within the study period
2. Currently receiving dialysis or anticipating requirement for dialysis
during the study period
3. Plasma oxalate > 30 μmol/L
4. Documented evidence of clinical manifestations of systemic oxalosis
(including pre-existing retinal, heart, or skin calcifications, or history of
severe bone pain, pathological fractures, or bone deformations)
5. Presence of any condition or comorbidities that would interfere with
study compliance or data interpretation or potentially impact patient
safety including, but not restricted to:
a. severe intercurrent illness
b. known causes of active liver disease/injury or transaminase elevation
(e.g., alcoholic liver disease, nonalcoholic fatty liver
disease/steatohepatitis)
c. physician concerns about intake of drugs of abuse or excessive alcohol
intake, or history of excessive alcohol intake in the 2 years prior to
enrollment (defined as ≥ 21 units of alcohol per week in men and ≥ 14
units of alcohol per week in women; where a "unit" of alcohol is
equivalent to a 12-ounce beer, 4-ounce glass of wine, or 1 ounce shot of
hard liquor)
d. history of serious mental illness that includes, but is not limited to,
schizophrenia, bipolar disorder, or severe depression requiring
hospitalization or pharmacological intervention
e. clinically relevant history or presence of cardiovascular, respiratory,
gastrointestinal, hematological, lymphatic, neurological,
musculoskeletal, genitourinary, immunological diseases, including
dermatological including rash, severe eczema or dermatitis, or
connective tissue diseases or disorders
Prior/Concomitant Therapy
6. Routine or chronic use of more than 3 grams of
acetaminophen/paracetamol daily
7. Use of an RNA interference (RNAi) drug within the last 6 months
8. History of one or more of the following reactions to an
oligonucleotide-based therapy:
a. Severe thrombocytopenia (platelet count ≤ 100,000/μL)
b. Hepatotoxicity, defined as alanine aminotransferase (ALT) or
aspartate aminotransferase (AST) > 3 times the upper limit of normal
(ULN) and total bilirubin > 2 × ULN or international normalized ratio
(INR) >1.5
c. Severe flu-like symptoms leading to discontinuation of therapy
d. Localized skin reaction from the injection (graded severe) leading to
discontinuation of therapy
e. Coagulopathy/clinically significant prolongation of clotting time
9. Participants receiving pyridoxine must have been at a stable dose for
at least 4 weeks prior to Day 1 and must be willing to remain on the
same stable dose throughout the study.
Prior/Concurrent Clinical Study Experience
10. Participation in any clinical study in which they received an
investigational medicinal product (IMP) within 4 months before
Screening
a. For IMPs with the potential to reduce urine and/or plasma oxalate
concentrations, these concentrations must have returned to historical
baseline levels prior to Screening
Diagnostic assessments
11. Liver function test abnormalities: ALT and/or AST >1.5 × ULN for age
and gender
12. Positive screening for hepatitis B surface antigen (HBsAg), antihepatitis
C virus (HCV) antibodies, or anti-human immunodeficiency
virus (HIV) 1 and 2 antibodies. If participant has been tested in the past 3 months, medical record documentation of this testing can be used for screening.Viral serology testing not required in participants <18 years of age.
13. Positive urine drug screen (to include at minimum: amphetamines,
barbiturates, cocaine, opiates, and benzodiazepines). Investigator
discretion is allowed. Urine drug screening is not required in participants
≤ 12 years of age.
Other Exclusions
14. Known hypersensitivity to DCR PHXC, or any of its ingredients
15. Inability or unwillingness to comply with the specified study procedures, including collection of 24-hour urine samples, and the
lifestyle considerations detailed in Section 5.3 |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of participants with a reduction from baseline in 24-hour Uox of at least 70%, based on an AUC and/or reaching normalization or near-normalization of 24-hour Uox on at least 2 consecutive visits,
starting from Day 90. Normalization of Uox is defined as < 0.46 mmol/24
hours; near-normalization is defined as ≥ 0.46 to < 0.60 mmol/24 hours
(values adjusted per 1.73 m2 BSA in participants aged < 18 years). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
An interim analysis may be conducted upon completion of two-thirds of
the participants for the purpose of re-evaluation of sample size. The
interim unblinded analysis will be performed by an independent
statistician other than the person responsible for the primary analysis of
this study and treatment codes will be revealed to that party only. A
minimal fraction of alpha (0.0001) will be spent at the interim analysis,
as the trial will not be stopped early for efficacy or futility based on the
results from the interim analysis. The final analysis will use 2.49% for
the primary endpoint, in order to preserve an overall type I error at the
1-sided 2.5% level. |
|
E.5.2 | Secondary end point(s) |
Key Secondary: AUC from Day 90 to Day 180, based on percent
change from Baseline in 24-hour Uox
Secondary:
1. Percent change in the summed surface area and number of kidney
stones identified via kidney ultrasound from Baseline to Day 180
2. Percent change in plasma oxalate from Baseline to Day 180 (for adults only)
3. Rate of change in eGFR from Baseline to Day 180
4. AE and SAE; change from Baseline in 12 lead ECG, physical
examination findings, vital signs, and clinical laboratory tests
5. Population and individual PK parameters for DCR PHXC and its metabolites |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
An interim analysis may be conducted upon completion of two-thirds of the participants for the purpose of re-evaluation of sample size. The
interim unblinded analysis will be performed by an independent
statistician other than the person responsible for the primary analysis of this study and treatment codes will be revealed to that party only. A
minimal fraction of alpha (0.0001) will be spent at the interim analysis,
as the trial will not be stopped early for efficacy or futility based on the results from the interim analysis. The final analysis will use alpha of 0.0249 for the primary endpoint, in order to preserve an overall type I error at the 1-sided 0.025 level. |
|
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
Australia |
Canada |
Egypt |
France |
Germany |
Israel |
Italy |
Japan |
Lebanon |
Netherlands |
New Zealand |
Poland |
Romania |
Saudi Arabia |
Spain |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial globally. |
|
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 | 3 |
E.8.9.1 | In the Member State concerned days | 16 |
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 | 6 |