Serious Bacterial Infection Clinical Trial
Official title:
A PROSPECTIVE, RANDOMIZED,OPEN-LABEL, COMPARATIVE STUDY TO ASSESS THE EFFICACY, SAFETY AND TOLERABILITY OF AZTREONAM- AVIBACTAM (ATM-AVI) AND BEST AVAILABLE THERAPY FOR THE TREATMENT OF SERIOUS INFECTIONS DUE TO MULTI-DRUG RESISTANT GRAM- NEGATIVE BACTERIA PRODUCING METALLO -Β-LACTAMASE (MBL)
| Verified date | January 2024 |
| Source | Pfizer |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
Phase 3 study to determine the efficacy, safety, and tolerability of aztreonam- avibactam (ATM- AVI) versus best available therapy (BAT) in the treatment of hospitalized adults with complicated intra-abdominal infections (cIAI), nosocomial pneumonia (NP) including hospital acquired pneumonia (HAP) and ventilator associated pneumonia (VAP), complicated urinary tract infections (cUTI), or bloodstream infections (BSI) due to metallo-β-lactamase (MBL)- producing Gram-negative bacteria.
| Status | Terminated |
| Enrollment | 15 |
| Est. completion date | January 23, 2023 |
| Est. primary completion date | January 23, 2023 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | Inclusion Criteria All Subjects 1. Subject must be =18 years of age. 2. Evidence of a personally signed and dated informed consent document indicating that the subject or a legally acceptable representative has been informed of all pertinent aspects of the study. 3. Subjects must have a confirmed diagnosis of serious bacterial infection, specifically cIAI, HAP/VAP, cUTI, or BSI requiring administration of IV antibacterial therapy. 4. Subjects must have an MBL- positive Gram- negative bacteria (an Enterobacteriaceae and/or Stenotrophomonas maltophilia for which the imipenem or meropenem MIC is = 4 µg/mL), that was isolated from an appropriate specimen obtained within 7 days prior to screening. 5. Female subject of childbearing potential must have a negative serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL. 6. Subjects who have received more than 48 hours of an appropriate prior systemic antibiotic[s] for a carbapenem non -susceptible pathogen may be enrolled if they demonstrate worsening or lack of improvement of objective symptoms or signs of infection (Note: antibiotic[s] is considered appropriate if microbiological susceptibility test results show that all carbapenem non -susceptible pathogens are susceptible to the systemic antibiotic[s] received). Additional Inclusion Criteria- cIAI Subjects 1. Subject must have a specimen obtained from an abdominal source during a surgical intervention within 7 days prior to screening from which a study qualifying pathogen was isolated upon culture. Surgical intervention includes open laparotomy, percutaneous drainage of an abscess, or laparoscopic surgery. 2. The subject has at least 1 of the following diagnosed during the surgical intervention: • Cholecystitis with gangrenous rupture or perforation or progression of the infection beyond the gallbladder wall; • Diverticular disease with perforation or abscess; - Appendiceal perforation or peri-appendiceal abscess; - Acute gastric or duodenal perforations, only if operated on >24 hours after diagnosis; - Traumatic perforation of the intestines, only if operated on >12 hours after diagnosis; - Other secondary peritonitis (not primary/ spontaneous bacterial peritonitis associated with cirrhosis or chronic ascites); - Intra abdominal abscess (including of the liver and spleen provided that there is extension beyond the organ with evidence of intra peritoneal involvement). 3. Subject has at least 1 of the following signs / symptoms from each of the following 2 groups: • Group A: Evidence of systemic inflammatory response: • Documented fever (defined as body temperature =38°C) or hypothermia (with a rectal core body temperature =35°C); • Elevated white blood cells (WBC) (>12000 cells/µL); • Systolic blood pressure (SBP) <90 mmHg or mean arterial pressure (MAP) <70 mmHg, or a SBP decrease of >40 mmHg; • Increased heart rate ( >90 beats per minute [bpm]) and respiratory rate (>20 breaths/min); • Hypoxemia (defined as oxygen [O2] saturation <95% by pulse oximetry); • Altered mental status. • Group B: Physical findings consistent with intra abdominal infection, such as: • Abdominal pain and/or tenderness, with or without rebound; • Localized or diffuse abdominal wall rigidity; • Abdominal mass. Additional Inclusion Criteria - HAP/VAP Subjects 1. Onset of symptoms >48 hours after admission or <7 days after discharge from an inpatient care facility (for which the duration of admission was >3 days). 2. New or worsening infiltrate on chest X- ray (or computerized tomography [CT]- scan) obtained within 48 hours prior to randomization. 3. At least 1 of the following: - Documented fever (temperature =38°C) or hypothermia (rectal/core temperature =35°C); - WBC =10,000 cells/mm3, leukopenia with total WBC =4500 cells/mm3, or >15% immature neutrophils (bands) noted on peripheral blood smear. 4. At least 2 of the following: • A new cough (or worsening of cough at Baseline); • Production of purulent sputum or purulent endotracheal secretions; • Auscultatory finding consistent with pneumonia/pulmonary consolidation (eg, rales, rhonchi, bronchial breath sounds, dullness on percussion, egophony); • Dyspnea, tachypnea, or hypoxemia (O2 saturation <90% or partial pressure of O2 [pO2]<60 mmHg while breathing room air); • Need for acute changes in the ventilator support status/system to enhance oxygenation, as determined by worsening oxygenation (arterial blood gas [ABG] or pO2 in arterial blood [PaO2]/fraction of inspired O2 [FiO2]) or needed changes in the amount of positive end expiratory pressure. 5. Subjects must have a respiratory specimen obtained within 7 days prior to screening for Gram stain and culture from which a study qualifying pathogen was isolated upon culture. This includes culture of either an expectorated sputum or a specimen of respiratory secretions obtained by endotracheal aspiration in intubated subjects, or by bronchoscopy with bronchoalveolar lavage (BAL), mini BAL or protected specimen brush (PSB) sampling. Additional Inclusion Criteria - cUTI Subjects 1. Subject had urine within 7 days prior to screening that cultured positive; containing =10^5 colony forming unit (CFU)/mL of at least 1 carbapenem non susceptible, MBL positive Gram-negative bacteria, ie, the isolate from the study qualifying culture. 2. Subject had pyuria in the 7 days prior to screening as determined by a midstream clean catch or catheterized urine specimen with =10 white blood cells (WBCs) per HighPower Field (HPF) on standard examination of urine sediment or =10 WBCs/mm3 in unspun urine. 3. Subject demonstrates either acute pyelonephritis or complicated lower UTI without pyelonephritis as defined by the following criteria: a. Acute pyelonephritis indicated by flank pain (which must have onset or worsened within 7 days of enrollment) or costovertebral angle tenderness on examination and at least 1 of the following: i) Fever, defined as body temperature =38°C (with or without patient symptoms of rigor, chills, or warmth); ii) Nausea and/or vomiting. OR b. Complicated lower UTI, as indicated by qualifying symptoms plus at least 1 complicating factor as follows: i) Qualifying symptoms: subject must have at least 2 of the following symptoms with at least 1 symptom from Group A: • Group A symptoms include dysuria, urgency, frequency, and or suprapubic pain; • Group B symptoms include fever (defined as body temperature =38°C with or without patient symptoms of rigor, chills, warmth), nausea, and/or vomiting. ii) Complicating factors: subject must have at least 1 of the following complicating factors: • Documented history of urinary retention (male subjects); • Obstructive uropathy that is scheduled to be medically or surgically relieved during study therapy and before the EOT; • Functional or anatomical abnormality of the urogenital tract, including anatomic malformations or neurogenic bladder, or with a postvoid residual urine volume of at least 100 mL; • Use of intermittent bladder catheterization or presence of an indwelling bladder catheter for at least 48 hours; • Urogenital procedure (such as cystoscopy or urogenital surgery) within the 7 days prior to obtainment of the specimen used for the study qualifying culture. Additional Inclusion Criteria - BSI Subjects 1. Subject has a confirmed diagnosis of primary BSI or catheter related BSI (CR- BSI). 2. Signs and symptoms of systemic infection characterized by at least one of the following: 1. Chills, rigors, or fever (temperature of =38.0°C or =100.4°F); 2. Elevated white blood cell count (=10,000/mm3) or left shift (>15% immature polymorphonuclear leukocytes (PMNs)). Exclusion Criteria All Subjects 1. History of serious allergic reaction (anaphylaxis, angioedema, bronchospasm, hypersensitivity) to any systemic antibacterial allowed per protocol. 2. Subject has a concurrent infection that may interfere with the evaluation of response to the study antibiotics. 3. Subject has a need for effective concomitant systemic antibacterials in addition to those allowed per protocol for the diagnoses under study. 4. Estimated CrCL =15 mL/min or anticipated requirement for dialysis during the study. Additional Exclusion Criteria - cIAI Subjects 1. Subject has infections limited to the hollow viscous, such as simple cholecystitis, gangrenous cholecystitis without rupture, and simple appendicitis, or has acute suppurative cholangitis, infected necrotizing pancreatitis, or pancreatic abscess. 2. Subject has abdominal wall abscess or small bowel obstruction without perforation or ischemic bowel without perforation. 3. Subject has a cIAI managed by staged abdominal repair (STAR), or "open abdomen" technique, or marsupialization. This criterion is intended to exclude subjects in whom the abdomen is left open, particularly those for whom re operation is planned. Additional exclusion criteria - cUTI Subjects 1. Subjects with suspected or confirmed complete obstruction of any portion of the urinary tract, perinephric or intrarenal abscess, or prostatitis, or history of any illness that, in the opinion of the investigator, may confound the results of the study or pose additional risk in administering the study therapy to the subject. 2. Any recent history of trauma to the pelvis or urinary tract. Additional exclusion criteria - BSI Subjects 1. Subject has a prosthetic cardiac valve or synthetic endovascular graft. 2. Subject has a suspected or documented medical condition with well-defined requirement for prolonged antibiotic treatment (eg, infectious endocarditis, osteomyelitis/septic arthritis, undrainable/undrained abscess, unremoveable/unremoved prosthetic associated infection). |
| Country | Name | City | State |
|---|---|---|---|
| Argentina | Hospital San Roque | Cordoba | |
| China | Baotou Central Hospital | Baotou | Inner Mongolia Autonomous Region |
| China | Hunan Province People's Hospital | Changsha | Hunan |
| China | The First Hospital of Kunming | Kunming | Yunnan |
| China | The First Hospital of Kunming | Kunming | |
| China | Huashan Hospital Fudan University | Shanghai | Shanghai |
| China | The First Affiliated Hospital of Shantou University Medical College | Shantou | Guangdong |
| Greece | General and Chest Diseases Hospital "Sotiria" | Athens | |
| Greece | General Hospital of Athens "Evangelismos" | Athens | |
| Greece | General Hospital of Athens "Laiko", | Athens | |
| Greece | University General Hospital "ATTIKON", Medicine and Infectious Diseases | Athens | |
| Greece | University General Hospital of Heraklion | Heraklion, Crete | |
| Greece | University General Hospital of Larissa | Larissa | |
| India | Victoria Hospital, Bangalore Medical College and Research Institute | Bangalore | |
| India | Apollo Hospitals Enterprise Limited | Chennai | Tamil NADU |
| India | S.R.Kalla Memorial Gastro & General Hospital | Jaipur | Rajasthan |
| India | Government medical College | Kozhikode | Kerala |
| India | Deenanath Mangeshkar Hospital And Research Centre | Pune | Maharashtra |
| Malaysia | Hospital Kuala Lumpur | Kuala Lumpur | Wilayah Persekutuan Kuala Lumpur |
| Malaysia | University Malaya Medical Centre | Kuala Lumpur | |
| Mexico | Hospital Civil de Guadalajara "Fray Antonio Alcalde" | Guadalajara | Jalisco |
| Philippines | Davao Doctors Hospital | Davao City | |
| Philippines | Makati Medical Center | Makati City | |
| Philippines | Manila Doctors Hospital | Manila | |
| Philippines | St. Luke's Medical Center | Quezon City | |
| Romania | Institutul National de Boli Infectioase "Prof. Dr. Matei Bals" | Bucuresti | |
| Romania | Spitalul Clinic de Boli Infectioase si Tropicale "Dr. Victor Babes" | Bucuresti | |
| Romania | Spitalul Clinic de Boli Infectioase Cluj Napoca | Cluj-Napoca | |
| Romania | Spitalul Clinic de Boli Infectioase "Sf. Parascheva" Iasi | Iasi | |
| Romania | Spitalul Clinic Judetean de Urgenta "Pius Brinzeu" | Timisoara | |
| Russian Federation | SBHI of the city of Moscow "N.I.Pirogov City Clinical Hospital # 1" | Moscow | |
| Russian Federation | FSBEI of HE "Smolensk State Medical University" of the Ministry of Health of the RF | Smolensk | |
| Russian Federation | OGBUZ "Smolensk Regional Clinical Hospital" | Smolensk | |
| Russian Federation | SRI of Antimicrobial Chemotherapy | Smolensk | |
| Taiwan | Kaohsiung Veterans General Hospital | Kaohsiung | |
| Taiwan | Kaohsiung Medical University Chung-Ho Memorial Hospital | Kaohsiung City | |
| Taiwan | National Taiwan University Hospital | Taipei City | |
| Thailand | Faculty of Medicine Siriraj Hospital | Bangkoknoi | Bangkok |
| Thailand | Songklanagarind Hospital, Prince of Songkla University | Hat Yai | Songkhla |
| Thailand | Bamrasnaradura Infectious Disease Institute (BIDI) | Muang | Nonthaburi |
| Thailand | Srinagarind Hospital, Division of lnfectious Disease and Tropical Medicine | Muang | Khonkaen |
| United States | Banner University Medical Center Tucson | Tucson | Arizona |
| Lead Sponsor | Collaborator |
|---|---|
| Pfizer | Allergan |
United States, Argentina, China, Greece, India, Malaysia, Mexico, Philippines, Romania, Russian Federation, Taiwan, Thailand,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Percentage of Participants With Clinical Cure at the Test of Cure (TOC) Visit -Microbiological Intent to Treat (Micro-ITT) Analysis Set | Clinical cure was defined as improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for the index infection (i.e., cIAI, cUTI, HAP/VAP or BSI) after study treatment. Also for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. The clinical response assessment was determined by a blinded independent adjudication committee. 95% confidence interval (CI) was calculated using Jeffrey's method. | Day 28 | |
| Secondary | Percentage of Participants With Clinical Cure at the TOC Visit-Microbiologically Evaluable (ME) Analysis Set | Clinical cure was defined as improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for the index infection (i.e., cIAI, cUTI, HAP/VAP or BSI) after study treatment. Also, for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. The clinical response assessment was determined by a blinded independent adjudication committee. 95% CI was calculated using Jeffrey's method. | Day 28 | |
| Secondary | Percentage of Participants With Clinical Cure at the End of Treatment (EOT) Visit- Micro-ITT Analysis Set | Clinical cure was defined as improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for the index infection (i.e., cIAI, cUTI, HAP/VAP or BSI) after study treatment. Also for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. The clinical response assessment was determined by a blinded independent adjudication committee. 95% CI was calculated using Jeffrey's method. | Up to 24 hours after the last infusion on Day 14 | |
| Secondary | Percentage of Participants With Clinical Cure at the EOT Visit- ME Analysis Set | Clinical cure was defined as improvement in baseline signs and symptoms such that no further antimicrobial treatment was required for the index infection (i.e., cIAI, cUTI, HAP/VAP or BSI) after study treatment. Also for cIAI participants, no unplanned drainage or surgical intervention was necessary since the initial procedure. The clinical response assessment was determined by a blinded independent adjudication committee. 95% CI was calculated using Jeffrey's method. | Up to 24 hours after the last infusion on Day 14 | |
| Secondary | Percentage of Participants With a Favorable Per Participant Microbiological Response at EOT Visit-Micro-ITT Analysis Set | Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification <10^3 colony forming units per milliliter [CFU/mL] for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). | Up to 24 hours after the last infusion on Day 14 | |
| Secondary | Percentage of Participants With a Favorable Per Participant Microbiological Response at TOC Visit-Micro-ITT Analysis Set | Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification <10^3 colony forming units per milliliter [CFU/mL] for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). | Day 28 | |
| Secondary | Percentage of Participants With a Favorable Per Participant Microbiological Response at EOT Visit-ME Analysis Set | Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification <10^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). | Up to 24 hours after the last infusion on Day 14 | |
| Secondary | Percentage of Participants With a Favorable Per Participant Microbiological Response at TOC Visit-ME Analysis Set | Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification <10^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). | Day 28 | |
| Secondary | Percentage of Pathogens According to Favourable Per-Pathogen Microbiological Response at the EOT Visit-Micro-ITT Analysis Set | Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification <10^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). | Up to 24 hours after the last infusion on Day 14 | |
| Secondary | Percentage of Pathogens According to Favourable Per-Pathogen Microbiological Response at the TOC Visit-Micro-ITT Analysis Set | Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification <10^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). | Day 28 | |
| Secondary | Percentage of Pathogens According to Favourable Per-Pathogen Microbiological Response at the EOT Visit-ME Analysis Set | Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification <10^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). ME analysis set comprised of participants from micro-ITT who received at least 48 hours or <48 hours of study therapy before discontinuation due to AE, no concomitant antibiotics against baseline MBL positive pathogens between 1st dose and TOC (excluding those with failed study therapy requiring additional antibiotics), had baseline organisms confirmed by central microbiological testing (except when locally confirmed); no indeterminate clinical outcomes at TOC. | Up to 24 hours after the last infusion on Day 14 | |
| Secondary | Percentage of Pathogens According to Favourable Per-Pathogen Microbiological Response at the TOC Visit-ME Analysis Set | Favorable microbiological response was defined as eradication or presumed eradication. Eradication was defined as absence (or urine quantification <10^3 CFU/mL for cUTI participants) of causative pathogen from an appropriately obtained specimen at the site of infection. Presumed eradication was defined as repeat culture of specimens were not performed/clinically indicated in a participant who had a clinical response of cure (specific to cIAI and HAP/VAP participants). ME analysis set comprised of participants from micro-ITT who received at least 48 hours or <48 hours of study therapy before discontinuation due to AE, no concomitant antibiotics against baseline MBL positive pathogens between 1st dose and TOC (excluding those with failed study therapy requiring additional antibiotics), had baseline organisms confirmed by central microbiological testing (except when locally confirmed); no indeterminate clinical outcomes at TOC. | Day 28 | |
| Secondary | Percentage of Participants Who Died Within 28 Days From Randomization-ITT Analysis Set | Percentage of participants who died due to any cause on or before 28 days after randomization were reported in this outcome measure. | From randomization up to Day 28 | |
| Secondary | Percentage of Participants Who Died Within 28 Days From Randomization- Micro ITT Analysis Set | Percentage of participants who died due to any cause on or before 28 days after randomization were reported in this outcome measure. | From randomization up to Day 28 | |
| Secondary | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events | An adverse event (AE) was any untoward medical occurrence in a study participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. A serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/ incapacity; resulted in congenital anomaly/birth defect; considered an important medical event. Treatment-emergent adverse event (TEAE) was any AE that started after the study medication start date and time. | From first dose of study treatment (Day 1) until late follow-up visit (Up to Day 45) | |
| Secondary | Number of Participants With Vital Sign Abnormalities | Vital signs included blood pressure and heart rate and were measured in a supine position after at least 10 minutes of rest for the participants. Criteria for vital sign abnormalities included: systolic blood pressure (SBP): value >150 millimeters of mercury (mmHg) and increase from baseline >=30 mmHg and value <90 and decrease from baseline =30. Diastolic BP (mm Hg) Value >100 and increase from baseline >= 20 and Value <50 and decrease from baseline >=20. Heart Rate (beats per minute [BPM]): Value <40 or >120. | From first dose of study treatment (Day 1) until TOC (Up to Day 28) | |
| Secondary | Number of Participants With Abnormal Physical Examination Findings | Physical examination included assessment of the following: abdomen, cardiovascular, ears, eyes, general appearance, head, lungs, lymph nodes, musculoskeletal, neurological, nose, skin and throat. Number of participants with abnormal physical examination findings for each body system is reported in this outcome measure. | Baseline (last non-missing value observed before start of treatment on Day 1), EOT (Up to 24 hours after the last infusion on Day 14), TOC (Day 28) | |
| Secondary | Number of Participants With Clinically Significant Abnormalities in Hematology Assessments | Potential clinically significant criteria included: Hematocrit <0.7*lower limit of normal (LLN) and >30% Decrease from Baseline or >1.3*upper limit of normal (ULN) and >30% Increase from Baseline; Hemoglobin: <0.7*LLN and >30% Decrease from Baseline and>1.3*ULN and >30% Increase from Baseline;;Erythrocytes: <0.7*LLN and >30% Decrease from Baseline or >1.3*ULN and >30% Increase from Baseline; Leukocytes: <0.65*LLN and >60% Decrease from Baseline or >1.5*ULN and >100% Increase from Baseline; Basophils/Leukocytes, Eosinophils/Leukocytes and Monocytes/Leukocytes: >4.0*ULN and>300% Increase from Baseline; Lymphocytes/Leukocytes <0.25*LLN and >75% Decrease from Baseline and >1.5* ULN and >100% Increase from Baseline; Neutrophils/Leukocytes: <0.65*LLN and >75% Decrease from Baseline or >1.6*ULN and >100% Increase from Baseline; Platelets<0.65*LLN and >50% Decrease from Baseline or >1.5*ULN and >100% Increase from Baseline. | From first dose of study treatment (Day 1) until TOC (Up to Day 28) | |
| Secondary | Number of Participants With Clinically Significant Abnormalities in Clinical Chemistry Assessments | Criteria for potential clinically significant results were: Aspartate Aminotransferase and Alanine Aminotransferase: >3.0* ULN and >100% increase from baseline (IFB); Bilirubin: >1.5* ULN and >100% IFB; Direct Bilirubin: >2.0* ULN and >150% IFB; Alkaline Phosphatase: 80% decrease from baseline (DFB) and >3.0* ULN and >100% IFB; Urea Nitrogen:100% DFB and >3.0* ULN and >200% IFB; Creatinine >2.0* ULN and >100% IFB; Sodium :10% DFB or >1.1* ULN and >10% IFB; Potassium: 20% DFB or >1.2* ULN and >20% IFB; Chloride: 20% DFB or >1.2*ULN and >20% IFB; Bicarbonate: 40% DFB or >1.3* ULN and >40% IFB; Calcium: 30% DFB or >1.3* ULN and >30% IFB; Albumin: 50% DFB or >1.5* ULN and >50% IFB; Glucose: 40% DFB or >3.0*ULN and >200% IFB. | From first dose of study treatment (Day 1) until TOC (Up to Day 28) | |
| Secondary | Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) | A standard 12-lead ECG was recorded with the participant in a supine position after at least 10 minutes of rest. The following ECG parameters were recorded: heart rate, PR-interval, QRS-duration, QT-interval, QTc-interval, RR interval. Clinical significance of ECG abnormalities was judged by Investigator. | From first dose of study treatment (Day 1) until TOC (Up to Day 28) |