| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Alpha-1 Antitrypsin Deficiency |
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| E.1.1.1 | Medical condition in easily understood language |
| Alpha-1 Antitrypsin Deficiency |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| 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 |
| To evaluate the safety and tolerability of PHP-303 20 mg QD versus PHP-303 10 mg QD versus placebo |
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| E.2.2 | Secondary objectives of the trial |
| To characterize the PK of PHP-303 20 mg QD versus PHP-303 10 mg QD |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Willing and able to provide signed and dated IEC-approved ICF prior to any study-related procedures and/or assessments being performed.
2. Willing and able to comply with protocol requirements, visit schedule, and protocol-stated restrictions for the duration of study participation.
3. Must agree to abstain from smoking and/or vaping from the time of screening through end of study.
4. Diagnosis of AATD as defined by serum AAT level < 11 µM (0.5 g/L) by documentation or by testing during Screening.
5. Pi*ZZ phenotype/genotype or Pi*Null phenotype/genotype by historical documentation or by testing during Screening. Other genotypes may be considered after discussion with the Medical Monitor.
6. Male or female participants ≥ 18 years of age at the time of signing the ICF.
7. Diagnosis of emphysema confirmed by historical CT scan.
8. Post bronchodilator FEV1 ≥ 35% of predicted during Screening (the FEV1 assessment can be repeated for confirmation purposes during Screening, provided the spirometry maneuvers are assessed as not meeting ATS/ ERS criteria as determined by the Investigator). FEV1 prior to randomization on dosing day (Day 1) must be ≥ 35% predicted. If below 35%, Investigator should determine if there is a medical reason for deterioration. Such participants may be re-screened when stable.
9. Adequate bone marrow, cardiac, liver, pancreatic, and renal function, as assessed by the following laboratory requirements to be conducted within 14 days prior to start of study drug (laboratory test(s) that do not meet the criteria can be repeated a single time during Screening):
a. Hemoglobin ≥ 9.0 g/dL
b. absolute neutrophil count (ANC) ≥ 1500/L
c. Platelet count ≥ 100,000/L
d. Total bilirubin < 1.3 mg/dL; participants with Gilbert’s syndrome may be enrolled with a total bilirubin ≤ 3.0 × ULN
e. ALT and AST ≤ 2 ULN, serum creatinine ≤ 1.5 ULN
f. PT-INR and PTT ≤ 1.5× ULN
g. Amylase/lipase WNL
h. Creatinine phosphokinase – WNL
i. Serum troponin I and T - WNL if tested in participants with elevated CPK MB fraction
j. Calculated GFR > 40 mL/min/1.73 m2 using the Cockcroft-Gault formula for creatinine clearance (weight should be corrected for BSA)
10. Has not received other forms of an experimental treatment (such as an investigational drug, new chemical entity and/or augmentation therapy) within a wash-out period of 5 half-lives of that treatment or 31 days, whichever is longer, and willing to forego such treatments for the duration of study participation.
11. All acute toxicities related to prior treatment recovered to Grade ≤ 1.
12. A female participant must meet one of the following criteria as recommended by the Clinical Trial Facilitation Group:
a. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant)
Participant is of non-childbearing potential, defined as surgically sterile (i.e., has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or is in a post-menopausal state (i.e., at least 1 year without menses prior to start of study drug).
b. Participant is of childbearing potential
If female of childbearing potential, negative serum pregnancy test performed within 7 days prior to start of study drug.
WOCBP must use highly effective methods of contraception (defined as those resulting in a failure rate of < 1% per year when used consistently and correctly) from signing of ICF, through duration of study treatment and for at least 45 days after last dose of study drug. The contraceptive methods that are considered highly effective are as follows:
• True abstinence from heterosexual intercourse from signing of ICF, through duration of study treatment, and for at least 45 days after the last dose of study medication. True abstinence: when it is in line with the preferred and usual lifestyle of the subject. Abstinence is considered a highly effective method only if participant refrains from heterosexual intercourse during the entire period of risk associated with the study treatments
• Male partner sterilization (vasectomized partner has received medical assessment of the surgical success) prior to the female participant’s entry into the study, and this male is the sole partner for that participant
• Intrauterine devices
• Hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal vaginal devices, or injections with prolonged release). There is no expected interaction between PHP-303 and these hormonal pills/devices
• Contraceptive methods that are not considered as highly effective include:
- male or female condom with or without spermicide
- occlusive cap (diaphragm or cervical/vault caps or sponge) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)
- progestogen-only oral hormonal contraceptives, where inhibition of ovulation is not the primary mode of action
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| E.4 | Principal exclusion criteria |
A participant who meets any of the following criteria will be excluded from study participation and will not be enrolled:
1. Diffuse interstitial lung diseases, cystic fibrosis, or clinically significant bronchiectasis as determined by the Investigator.
2. Uncontrolled asthma as determined by the Investigator.
a. Stable asthma, or past asthma diagnosis is not an exclusion criterion.
3. Acute exacerbation of underlying lung disease requiring oral steroids and/or antibiotics within 4 weeks of start of screening. If participants develop an acute exacerbation between screening and randomization, participants should not be randomized, and Screening should be disrupted. Participants may be rescreened when the acute exacerbation has stabilized or resolved.
4. Upper or lower respiratory tract infection within 4 weeks of start of screening. If participants develop an infection between screening and randomization, participants should not be randomized, and Screening should be disrupted. Participants may be considered for re-Screening, provided at least 2 weeks have lapsed since receiving last dose of antibiotics and provided their condition has stabilized.
5. Other acute illness within 4 weeks of start of screening. If participants develop an acute illness between screening and randomization, participants should not be randomized, and Screening should be disrupted. Participants may be considered for re-Screening, provided their condition has stabilized or resolved. When possible, Investigator is encouraged to contact the Medical Monitor to verify that participant can be re-screened.
6. Known seropositivity for HIV.
7. History of biopsy-proven cirrhosis or CT-evidence of possible cirrhosis, e.g., nodularity on CT, and/or clinical complications of cirrhosis (variceal bleeding, ascites, hepatic encephalopathy), and/or diagnosis of cirrhosis based on Investigator’s judgment.
8. History of pancreatitis.
9. Positive test results for chronic hepatitis B infection (defined as positive HBsAg serology)
a. Occult or prior hepatitis B infection (defined as positive total HBcAb and negative HBsAg) may be included.
b. Treatment with IVIG within 3 months of enrollment.
10. Positive test results for hepatitis C (HCV antibody serology testing) with detectable HCV RNA by RT-PCR.
a. Participants positive for HCV antibody are eligible only if RT-PCR is negative for HCV RNA.
11. Malignancy within the last 5 years. Exceptions include:
a. Curatively treated basal cell/squamous cell skin cancer.
b. Carcinoma in situ of the cervix.
c. Superficial transitional cell bladder carcinoma.
d. In situ ductal carcinoma of the breast after complete resection.
e. Localized, resected and/or low-risk prostate cancer could be eligible; to be discussed with the Medical Monitor.
12. Smoked and/or vaped within 6 months prior to Screening.
13. Prior bone marrow or solid organ transplantation.
14. Expected to receive a lung or liver transplant during the course of the study.
15. Scheduled for lobectomy or lung volume-reduction surgery.
16. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
17. Other major or uncontrolled medical conditions, e.g., myocardial infarction or NYHA Class III/IV heart failure within the last 6 months, stroke, uncontrolled diabetes, uncontrolled autoimmune disease, uncontrolled fungal, bacterial, and/or viral infection, active systemic infection.
18. QT interval corrected by Fridericia for heart rate (QTcF) interval of > 470 msec at screening, known history of congenital long QT syndrome, or are taking any medications within 7 days prior to start of study drug that are known to prolong the QT interval and/or are associated with a risk of Torsades de Pointes. A single retest during Screening is permissible for participants who fail this criterion.
19. Other concomitant experimental or unapproved therapy, including recreational drugs.
20. Known history of alcohol abuse or daily heavy alcohol consumption (defined as more than 14 units of alcohol per week for females and males). One unit of alcohol is equivalent to a half pint of beer, 1 measure of spirits or 1 glass of wine.
21. Requirement for immunosuppressive agents.
a. Oral prednisone of up to 20 mg per day or equivalent of other glucocorticoid is allowed, if medically indicated.
22. Requirement for drugs that are known strong inducers or inhibitors of CYP3A4 (Appendix A); treatment must be stopped a minimum of 2 weeks before the start of study drug).
23. Any medical conditions that, in the Investigator’s or Sponsor’s opinion, would impose excessive risk to the participant or ability to assess effect of the drug.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Frequency, severity, and relatedness of TEAEs and SAEs
• Changes from baseline in hematology and blood chemistry values
• Assessments of physical examinations, vital signs, and ECGs
|
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Levels of PHP-303 in sputum and plasma during treatment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | Yes |
| 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 | 3 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| Last visit of the last participant |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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