| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Autosomal Dominant Polycystic Kidney Disease |
| autoszomális domináns policisztás vesebetegség |
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| E.1.1.1 | Medical condition in easily understood language |
| Kidney disorder characterized by cyst formation and progressive enlargement in the kidney, liver, and other organs |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036046 |
| E.1.2 | Term | Polycystic kidney, autosomal dominant |
| E.1.2 | System Organ Class | 100000004850 |
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| 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 |
Primary Objective of Part 1:
•To demonstrate the efficacy of lixivaptan compared to placebo in the slowing of deterioration in kidney function in participants with ADPKD as demonstrated by the annualized change from baseline in estimated glomerular filtration rate (eGFR).
The key safety objective of Part 1:
•To compare the incidences of liver chemistry test elevations in participants randomized to lixivaptan with participants randomized to placebo.
Primary Objective of Part 2:
•To demonstrate the continued efficacy of lixivaptan in the slowing of deterioration in kidney function in participants randomized to lixivaptan in the double-blind phase (Part 1) as measured by the annualized change from baseline (Part 2) in eGFR at the end of the open-label phase (Part 2).
The key safety objective of Part 2:
•To assess the incidence of liver chemistry test abnormalities during the open-label phase.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of Part 1:
•To compare the rate of change (slope) in on-treatment eGFR in participants treated with lixivaptan to participants treated with placebo.
•To assess the effect of lixivaptan on total kidney volume (TKV) as measured by magnetic resonance imaging (MRI) compared to placebo.
The secondary safety objective of Part 1:
•To assess the non-hepatic safety and tolerability of lixivaptan.
The secondary objectives of Part 2 are:
•To assess the rate of change (slope) in on-treatment eGFR in Part 2 in participants treated with lixivaptan in Part 1 and Part 2;
•To assess the effect of lixivaptan on TKV as measured by MRI in Part 2 in participants treated
with lixivaptan in Part 1 and Part 2.
The secondary safety objective of Part 2:
•To assess the non-hepatic safety and tolerability of lixivaptan.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Male or female, between 18 and 60 years of age (inclusive) at the time of Screening (Visit 1a).
2.Diagnosis of ADPKD by modified Pei criteria:
•For participants with family history of ADPKD, by ultrasound:
- 18-39 years: ≥3 cysts, unilateral or bilateral;
- 40-59 years: ≥2 cysts in each kidney;
- 60 years: ≥4 cysts in each kidney; or
•For participants with family history of ADPKD, by computerized tomography (CT) or MRI:
- 18-40 years: ≥10 cysts in both kidneys; or
•For participants without family history of ADPKD
- a minimum of 10 cysts per kidney by any radiologic method and
exclusion of other cystic kidney diseases (multiple simple kidney
cysts, renal tubular acidosis, cystic dysplasia of the kidney,
multicystic kidney, multilocular cysts of the kidney, medullary
cystic kidney and acquired cystic disease of the kidney); or
- genetic diagnosis of ADPKD.
3.Mayo Clinic ADPKD classification of 1C, 1D, or 1E based on age and height-adjusted total kidney volume as determined by kidney MRI obtained during Screening, as assessed by the central imaging vendor.
4.eGFR ≥25 mL/min/1.73 m2 and ≤90 mL/min/1.73 m2 based on the mean of 2 eGFR determinations (Visits 1a and 2 or Visits 1b and 2, if Visit 1b is required) calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation
from serum creatinine values obtained during Screening (Appendix 1 (Section 13.1)) Note: This criterion will preliminarily be reviewed at Visit 2 based on Visit 1a or Visit 1b results (if Visit 1b is required). The criterion must be re-evaluated no later than Visit 3 when results for Visits 1a and 2 or Visits 1b and 2 are available.
5.Appropriate control of hypertension including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker (unless not considered appropriate for the participant) as suggested by the Kidney Disease Improving Global Outcomes (KDIGO) “Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease,” without the use of a diuretic.
6.Body mass index (BMI) between 18 and 40 kg/m2 (inclusive) at the time of Screening.
7.Female participants must:
a. not be pregnant, lactating, or breastfeeding.
b. be either postmenopausal (defined as amenorrhea for ≥ 12 months), surgically sterile (defined as having undergone hysterectomy and/or bilateral oophorectomy) or, if of child-bearing potential (WOCBP), agree to practice acceptable methods of birth control or remain abstinent (only if this is the usual and preferred lifestyle of the participant) during the full duration of the trial and for 30 days after the last dose of study drug. Birth control methods that can be used during the study include the following:
• hormonal contraception associated with inhibition of ovulation (i.e., oral, intravaginal, transdermal) progestogen-only hormonal contraception (i.e., oral, injectable, implantable)
• intrauterine device (IUD), including progestin-containing intrauterine devices
• intrauterine hormone-releasing system (IUS)
• male sexual partner who has been vasectomized for at least 3 months prior to Screening and who has obtained a follow-up negative sperm count and is the sole sexual partner
• bilateral tubal ligation
• Essure® procedure (tubal occlusion)
• male or female condom with spermicide (cream, spray, gel, suppository, or polymer film)
• diaphragm, cervical cap, or contraceptive sponge with spermicide (with or without male condom)
8.Male participants must agree to use an acceptable form of birth control (see list above) or remain abstinent (only if this is the usual and preferred lifestyle of the participant) during the full duration of the trial and for 30 days after the last dose of study drug.
9.Have read, understood, and provided written informed consent after the nature of the study has been fully explained and must be willing to comply with protocol requirements and study-related procedures.
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| E.4 | Principal exclusion criteria |
1.Advanced diabetes (e.g., glycosylated hemoglobin [HgbA1c] >7.5%, and/or glycosuria by dipstick, significant proteinuria [>300 mcg albumin/mg creatinine]), other significant kidney disease, kidney cancer, transplanted kidney, single kidney, kidney surgery within the past 6 months (including cyst drainage or fenestration) or acute kidney injury within 6 months prior to Screening.
2.Clinically significant incontinence, overactive bladder, or urinary retention (e.g., benign prostatic hyperplasia).
3.New York Heart Association Functional Class 3 or 4 heart failure or other significant cardiac or electrocardiogram (ECG) findings that could pose a safety risk to the participant.
4.History of infection with human immunodeficiency virus (HIV) unless the participant is stable and doing well on a non-CYP interacting ART regimen and the participant has not required more than 2 changes in their ART regimen since treatment inception.
5.History of clinically significant drug or alcohol abuse in the 2 years prior to Screening Visit 1a.
6.Contraindications to or interference with MRI assessments (e.g., ferromagnetic metal prostheses, aneurysm clips, severe claustrophobia, or large abdominal/back tattoos). Investigator should seek MRI safety guidance from the local MRI facility.
7.Any malignancy within 5 years prior to Screening except for basal cell carcinoma successfully treated with local therapy or malignancies that are considered by the Investigator not to affect participant survival (after discussion with the medical monitor).
8.Medical history or findings that preclude safe participation in the trial or participants who are likely to be non-compliant with trial procedures in the opinion of the Investigator or medical monitor.
9.Clinically significant liver disease or impairment or alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin values >1.2 x ULN during Screening. Note: This criterion will preliminarily be reviewed at Visit 2 based on Visit 1a and Visit 1b results (if Visit 1b is required). The criterion must be re-evaluated no later than Visit 3 when results for Visit 2 are available.
10.Requirement for ongoing diuretic use.
11.Participants who are currently taking, or are expected to be taking, strong or moderate CYP3A4 or CYP2C8 inhibitors or inducers including regular use of grapefruit juice, Seville oranges, or St. John’s wort. If applicable, there should be a 14-day washout of these treatments prior to Visit 2.
12.Prior use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor (e.g., canagliflozin, dapagliflozin, empagliflozin, etc.) within the 2 months prior to Screening Visit 1a or expected need for initiation of treatment with a SGLT2 inhibitor during the study.
13. Prior use of a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor within the 2 months prior to Screening Visit 1a or expected need for initiation of treatment with a HIF-PH inhibitor during the study.
14.Simvastatin at a total daily dose >10 mg or amlodipine at a total daily dose >5 mg.
15.Prior use of tolvaptan or lixivaptan within the 2 months prior to Screening Visit 1a.
16.Prior use of conivaptan, somatostatin analogs (e.g., lanreotide, pasireotide, octreotide, etc.), metformin (except for diabetes), nicotinamide, bardoxolone, demeclocycline, or mTOR kinase inhibitors (e.g., everolimus, sirolimus, etc.) within the 2 months prior to Screening Visit 1a.
17.Participants who have taken any investigational drug or used an investigational device within 30 days, or 5 half-lives, whichever is longer, prior to Screening Visit 1a or plan to participate in an interventional trial during the study.
18.Hypovolemia on physical examination at Screening.
19.Abnormal serum sodium concentration at Screening.
20.Positive test results for hepatitis B surface antigen (HBsAg).
21.Positive test results for hepatitis C (HCV) antibody (Anti-HCV), with the exception of participants for whom the reflex HCV RNA titer test is negative.
22.Known sensitivity or idiosyncratic reaction to lixivaptan and/or its excipients.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1:
•The primary endpoint is the annualized change in eGFR calculated from the CKD-EPI equation for serum creatinine from baseline (mean of 3 eGFR determinations obtained during Screening and Placebo Run-in Periods (Visits 1a/1b (if required), Visit 2, and Visit 3) to final assessment (mean of 3 eGFR determinations obtained during Follow-up Period I or, for participants who discontinue treatment prior to Visit 22, during the Follow-up Period 8 to 28 days following study drug treatment discontinuation).
Part 1 Key Safety Endpoint
•Incidence of serum ALT levels >3 x ULN in participants randomized to lixivaptan compared to those randomized to placebo.
Part 2 Key Comparison Endpoint
•The primary endpoint of Part 2 is the annualized change in eGFR calculated from the CKD-EPI equation for serum creatinine from baseline (mean of 3 eGFR determinations obtained during Follow-up Period I) to final assessment (mean of 3 eGFR determinations obtained during Follow-up Period II).
Part 2 Key Safety Endpoint:
•Incidence of serum ALT levels > 3 x ULN in participants exposed to lixivaptan in Part 2.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout this study, the safety of participants will be closely
monitored by an independent data monitoring committee (DMC). The
DMC will comprise three disease experts and a biostatistician and will be governed by a DMC Charter. A Data Monitoring Committee will review safety and study data at specified intervals for the duration of the study. |
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| E.5.2 | Secondary end point(s) |
Part 1:
•The annualized rate of change (slope) in on-treatment eGFR, based on all on-treatment eGFR determinations during the Double-Blind, Randomized Treatment Period in Part 1, calculated from the CKD-EPI equation for serum creatinine;
•The annualized rate of change from baseline in TKV, determined by MRI, during Follow-up Period I.
Secondary Safety and tolerability of lixivaptan assessed through evaluation of:
•Treatment-emergent adverse events (TEAEs);
•Clinical laboratory findings (clinical chemistry including additional analyses of liver chemistry, hematology and urinalysis);
•Vital signs;
•12-lead electrocardiograms (ECG).
Part 2:
•The annualized rate of change in eGFR (calculated from the CKD-EPI equation for serum creatinine) from baseline (mean of 3 eGFR determinations obtained during Follow-up Period I) to Follow-up Period II;
•The annualized rate of change in TKV determined by MRI.
Secondary Safety and tolerability of lixivaptan assessed through evaluation of:
•Treatment-emergent adverse events (TEAEs);
•Clinical laboratory findings (clinical chemistry including additional analyses of liver chemistry tests), hematology and urinalysis);
•Vital signs;
•12-lead electrocardiograms (ECG).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy endpoints will be displayed by study
visit, using summary statistics including the number of observations, the mean, median, standard deviation, and range for continuous measures and counts and percentages for categorical measures. Actual values as well as change from baseline will be presented.
Supportive and exploratory efficacy measures will be analyzed similarly as above. Details of the analysis methods will be outlined in the statistical analysis plan (SAP).
In addition, a responder analysis (based on change in serum bile acid
levels and bilirubin) will also be considered. The response definition and its appropriate analysis methodology will be outlined in the SAP for the study. |
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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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Study in two parts: Part 1 double blind placebo controlled and Part 2 open label |
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| 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
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Brazil |
| Canada |
| Chile |
| Colombia |
| Georgia |
| Israel |
| Mexico |
| Peru |
| Serbia |
| Turkey |
| Ukraine |
| United States |
| Belgium |
| Bulgaria |
| France |
| Hungary |
| Italy |
| Poland |
| Romania |
| Slovakia |
| Spain |
| United Kingdom |
| Argentina |
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| 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
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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