Safety and Efficacy of Solithromycin in Adolescents and Children With Community-Acquired Bacterial Pneumonia

• Sponsor: Melinta Therapeutics, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02605122
• Collaborator: Biomedical Advanced Research and Development Authority (U.S. Fed)
• Enrollment: 97
• Locations: 58
• Arms: 2
• Actual Duration (Months): 23.6
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a phase 2/3, randomized, open-label, active control, multi-center study to assess the safety and efficacy of solithromycin in children and adolescents with community-acquired bacterial pneumonia (CABP).

Condition or Disease	Intervention/Treatment	Phase
Community-acquired Bacterial Pneumonia	Drug: Solithromycin; Drug: Standard of Care	Phase 2/Phase 3

Detailed Description

Subjects who meet all inclusion/exclusion criteria and sign the informed consent/assent were enrolled. Subjects were randomized to receive solithromycin or a comparator antibiotic, administered IV and/or by mouth (PO) based on weight and age. Subjects were treated daily for 5 to 7 days with oral solithromycin and 5 to 7 days with IV or IV-to-oral solithromycin. Subjects were treated for 5 to 10 days with comparator antibiotics. Subjects received safety and efficacy assessments during and after treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 97 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Masking Description: A healthcare provider designated as a sub-investigator blinded to treatment allocation at the site documented clinical response at specified time points during the study.
• Primary Purpose: Treatment
• Official Title: A Phase 2/3, Randomized, Open-Label, Multi-center Study to Determine the Safety and Efficacy of Solithromycin in Adolescents and Children With Suspected or Confirmed Community-Acquired Bacterial Pneumonia
• Actual Study Start Date: Apr 1, 2016
• Actual Primary Completion Date: Mar 21, 2018
• Actual Study Completion Date: Mar 21, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Solithromycin Solithromycin will be administered orally, as capsules or as a suspension, or intravenously. Patients may receive intravenous therapy initially and switch to an oral formulation. Dosage is weight based and age based.	Drug: Solithromycin; Other Names: CEM-101
Active Comparator: Standard of Care Comparators will be selected according to subject age and are consistent with current recommendations for treatment of CABP in children. These include intravenous ceftriaxone, ampicillin, and amoxicillin and oral amoxicillin and amoxicillin-clavulanic acid. Azithromycin or erythromycin may be added as well.	Drug: Standard of Care; Age- and weight-based dosing as appropriate per sites standard of care.; Other Names: ceftriaxone ampicillin amoxicillin amoxicillin-clavulanic acid Azithromycin Erythromycin Erythromycin lactobionate

Outcome Measures

Primary Outcome Measures

1. Overview of Adverse Events By Treatment Arm [Up to 28 days post-treatment]

   Summary of subjects experiencing Treatment Emergent Adverse Events (TEAE) through Day 16 visit and Treatment Emergent Serious Adverse Events (TESAE) through Day 28 visit (28 days +/- 4 days after randomization)

Secondary Outcome Measures

1. Summary of Early Clinical Response [During Treatment Days 3 to 4]

   Early clinical response (ECR) was defined using the latest efficacy evaluation from Day 2 (if subject discharged prior to Day 2), Day3, or Day 4, and was defined as improvement in at least 1 presenting sign/symptom of CABP with no deterioration in any signs/symptoms of CABP and no requirement for an additional antibiotic.

2. Summary of Clinical Improvement [Last day of Treatment (+48 hours)]

   Clinical improvement was assessed using the latest efficacy evaluation conducted on last day of treatment (+48 hours), and was defined identically to the early clinical response.

3. Summary of Clinical Cure [Short-term follow-up at 16 days (+/- 4 days)]

   Clinical cure was assessed using the latest efficacy evaluation conducted on Day 16 (+/- 4 days) post-randomization, and was defined as resolution of all presenting signs/symptoms of CABP (excluding cough), no development of new signs/symptoms of CABP, and no requirement for an additional antibiotic.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Months to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• History of and/or documented fever (rectal, ear, or oral temperature ≥38°C or axillary temperature ≥37.5°C) or hypothermia (rectal, ear, or oral temperature <35°C or axillary temperature <34.5°C)

• Chest radiograph infiltrates consistent with bacterial pneumonia (or pneumonia caused by atypical bacterial agents); if a subject is outpatient and starting on oral therapy, a radiograph is not required.

• Presence of at least 2 of the following signs or symptoms:

• Cough

• Difficulty breathing

• Production of purulent sputum

• Chest pain

• Grunting

• Hypotension

• Tachycardia, defined as follows:

2 months to <24 months: ≥160 beats/min 24 months to <10 years: ≥140 beats/min

• 10 years: ≥100 beats/min

• Tachypnea, defined as follows:

2 months to <12 months: ≥50 breaths/min 12 months to <5 years: ≥40 breaths/min

• 5 years: ≥20 breaths/min

• Physical exam consistent with pulmonary consolidation

• Presence of at least 1 of the following:

• Leukocytosis (≥12,000 white blood cells [WBC]/mm3)

• Leukopenia (<5000 WBC/mm3)

• ≥10% immature neutrophils (bands) regardless of total peripheral WBC

• Elevated inflammatory markers (C-reactive protein or procalcitonin)

• Oxygen saturation <97% on room air

• Organism consistent with a typical respiratory pathogen identified

Exclusion Criteria:

• Ventilator-associated or hospital-acquired pneumonia

• 48 hours of systemic antibacterial therapy

• confirmed or suspected bacterial meningitis

• breast-feeding females

• positive pregnancy test

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Little Rock	Arkansas	United States	72202
2		Los Angeles	California	United States	90095
3		Sacramento	California	United States	95817
4		San Diego	California	United States	92123
5		Washington	District of Columbia	United States	20010
6		Tampa	Florida	United States	33606
7		Louisville	Kentucky	United States	40202
8		Omaha	Nebraska	United States	68198-2162
9		Las Vegas	Nevada	United States	89102
10		Durham	North Carolina	United States	27710
11		Greenville	North Carolina	United States	27834
12		Toledo	Ohio	United States	43606
13		Portland	Oregon	United States	97239
14		Hershey	Pennsylvania	United States	17033
15		Memphis	Tennessee	United States	38105
16		Amarillo	Texas	United States	79106
17		Houston	Texas	United States	77030
18		Splendora	Texas	United States	77372
19		Charlottesville	Virginia	United States	22905
20		Richmond	Virginia	United States	29298
21		Roanoke	Virginia	United States	24013
22		Pleven		Bulgaria	5800
23		Plovdiv		Bulgaria	4000
24		Ruse		Bulgaria	7002
25		Sofia		Bulgaria	1233
26		Sofia		Bulgaria	1407
27		Sofia		Bulgaria	1431
28		Vratsa		Bulgaria	3001
29		Budapest		Hungary	1083
30		Budapest		Hungary	1089
31		Budapest		Hungary	1097
32		Budapest		Hungary	1125
33		Cegléd		Hungary	2700
34		Debrecen		Hungary	4031
35		Gyor		Hungary	9024
36		Gyula		Hungary	5700
37		Mosdós		Hungary	7257
38		Nagykanizsa		Hungary	8800
39		Nyiregyhaza		Hungary	4400
40		Szeged		Hungary	6720
41		Szekesfehervar		Hungary	8000
42		Torokbalint		Hungary	2045
43		Veszprém		Hungary	8200
44		Caloocan City		Philippines	1400
45		Cebu City		Philippines	6000
46		Davao City		Philippines	8000
47		Iloilo		Philippines	5000
48		Manila		Philippines	1000
49		Muntinlupa		Philippines	1781
50		Quezon City		Philippines	1100
51		Quezon City		Philippines	1104
52		Esplugues de Llobregat	Barcelona	Spain	08950
53		San Sebastian	Guipuzcoa	Spain	20014
54		Barcelona		Spain	08035
55		Barcelona		Spain	08916
56		Madrid		Spain	28046
57		London		United Kingdom	N18 1QX
58		London		United Kingdom	SW17 0RE

Sponsors and Collaborators

• Melinta Therapeutics, Inc.
• Biomedical Advanced Research and Development Authority

Investigators

• Principal Investigator: Michael Cohen-Wolkowiez, MD, PhD, Duke Clinical Research Institute

Study Documents (Full-Text)

• Study Protocol - Nov 29, 2017
• Statistical Analysis Plan - May 14, 2018

More Information

Publications

None provided.

• Responsible Party: Melinta Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT02605122
• Other Study ID Numbers: CE01-203
• First Posted: Nov 16, 2015
• Last Update Posted: Jan 3, 2019
• Last Verified: Nov 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Melinta Therapeutics, Inc.: pneumonia; macrolide; pediatric
• Additional relevant MeSH terms: Pneumonia; Pneumonia, Bacterial; Amoxicillin; Azithromycin; Ceftriaxone; Erythromycin; Erythromycin Estolate; Erythromycin Ethylsuccinate; Erythromycin stearate; Ampicillin; Clavulanic Acids; Clavulanic Acid; Amoxicillin-Potassium Clavulanate Combination; Solithromycin; Erythromycin lactobionate

Study Results

Participant Flow

Recruitment Details	Subjects who met all inclusion/exclusion criteria and sign the informed consent/assent were enrolled. Subjects were randomized to receive solithromycin or a comparator antibiotic, administered IV and/or by mouth (PO) based on weight and age. Subjects received safety and efficacy assessments during and after treatment.

Arm/Group Title	Solithromycin	Standard of Care
Arm/Group Description	Solithromycin was dosed for 5-7 days. Orally, as capsules or as a suspension, or intravenously. Subjects could receive intravenous therapy initially and switch to an oral formulation.	Comparators were dosed according to age and were consistent with current recommendations for treatment of CABP in children per site standard of care.
Period Title: Overall Study
STARTED	73	24
Received Study Drug	70	24
COMPLETED	68	22
NOT COMPLETED	5	2

Baseline Characteristics

Arm/Group Title	Solithromycin	Standard of Care	Total
Arm/Group Description	Solithromycin was dosed for 5-7 days.	Comparators were does up to 10 days per site standard of care.	Total of all reporting groups
Overall Participants	70	24	94
Age (Count of Participants)
<=18 years	70 100%	24 100%	94 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9.48 (4.71)	9.65 (4.95)	9.57 (4.83)
Sex: Female, Male (Count of Participants)
Female	30 42.9%	11 45.8%	41 43.6%
Male	40 57.1%	13 54.2%	53 56.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 2.9%	2 8.3%	4 4.3%
Not Hispanic or Latino	65 92.9%	21 87.5%	86 91.5%
Unknown or Not Reported	3 4.3%	1 4.2%	4 4.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	12 17.1%	4 16.7%	16 17%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	11 15.7%	2 8.3%	13 13.8%
White	47 67.1%	16 66.7%	63 67%
More than one race	0 0%	1 4.2%	1 1.1%
Unknown or Not Reported	0 0%	1 4.2%	1 1.1%
Region of Enrollment (participants) [Number]
Hungary	19 27.1%	4 16.7%	23 24.5%
United States	18 25.7%	9 37.5%	27 28.7%
Philippines	12 17.1%	4 16.7%	16 17%
Bulgaria	21 30%	6 25%	27 28.7%
Spain	0 0%	1 4.2%	1 1.1%

Outcome Measures

1. Primary Outcome

Title	Overview of Adverse Events By Treatment Arm
Description	Summary of subjects experiencing Treatment Emergent Adverse Events (TEAE) through Day 16 visit and Treatment Emergent Serious Adverse Events (TESAE) through Day 28 visit (28 days +/- 4 days after randomization)
Time Frame	Up to 28 days post-treatment

Outcome Measure Data

Analysis Population Description

Treatment through Day 28 (28 days +/- 4days after randomization)

Arm/Group Title	Solithromycin	Standard of Care
Arm/Group Description	Solithromycin was dosed for 5-7 days.	Comparators were dosed up to 10 days per site standard of care.
Measure Participants	70	24
TEAE	24 34.3%	7 29.2%
TESAE	1 1.4%	1 4.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Solithromycin, Standard of Care
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion experiencing TEAE or TESAE
	Estimated Value	34.3
	Confidence Interval	(2-Sided) 95%; 23 to 47
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Summary of Early Clinical Response
Description	Early clinical response (ECR) was defined using the latest efficacy evaluation from Day 2 (if subject discharged prior to Day 2), Day3, or Day 4, and was defined as improvement in at least 1 presenting sign/symptom of CABP with no deterioration in any signs/symptoms of CABP and no requirement for an additional antibiotic.
Time Frame	During Treatment Days 3 to 4

Outcome Measure Data

Analysis Population Description

Not all subjects had the Early Clinical Improvement assessment performed.

Arm/Group Title	Solithromycin	Standard of Care
Arm/Group Description	Solithromycin was dosed for 5-7 days.	Comparators were dosed up to 10 days per site standard of care.
Measure Participants	51	15
Number (95% Confidence Interval) [percentage of participants]	66.7 95.3%	46.7 194.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Solithromycin, Standard of Care
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Achievement of ECR
	Estimated Value	62.1
	Confidence Interval	(2-Sided) 95%; 49 to 74
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Summary of Clinical Improvement
Description	Clinical improvement was assessed using the latest efficacy evaluation conducted on last day of treatment (+48 hours), and was defined identically to the early clinical response.
Time Frame	Last day of Treatment (+48 hours)

Outcome Measure Data

Analysis Population Description

Not all subjects had the Clinical Improvement assessment performed.

Arm/Group Title	Solithromycin	Standard of Care
Arm/Group Description	Solithromycin was dosed for 5-7 days.	Comparators were dosed up to 10 days per site standard of care.
Measure Participants	62	21
Number (95% Confidence Interval) [percentage of participants]	64.5 92.1%	81 337.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Solithromycin, Standard of Care
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Achievement of Clinical Improvement
	Estimated Value	68.7
	Confidence Interval	(2-Sided) 95%; 58 to 78
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Summary of Clinical Cure
Description	Clinical cure was assessed using the latest efficacy evaluation conducted on Day 16 (+/- 4 days) post-randomization, and was defined as resolution of all presenting signs/symptoms of CABP (excluding cough), no development of new signs/symptoms of CABP, and no requirement for an additional antibiotic.
Time Frame	Short-term follow-up at 16 days (+/- 4 days)

Outcome Measure Data

Analysis Population Description

Not all subjects had the Clinical cure assessment performed.

Arm/Group Title	Solithromycin	Standard of Care
Arm/Group Description	Solithromycin was dosed for 5-7 days.	Comparators were dosed up to 10 days per site standard of care.
Measure Participants	60	19
Number (95% Confidence Interval) [percentage of participants]	60.0 85.7%	68.4 285%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Solithromycin, Standard of Care
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Achievement of Clinical Cure
	Estimated Value	62
	Confidence Interval	(2-Sided) 95%; 50 to 73
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Up to 32 days
Arm/Group Title	Solithromycin		Standard of Care
Arm/Group Description	Solithromycin was dosed for 5-7 days.		Comparators were dosed up to 10 days per sites standard of care.
All Cause Mortality
	Solithromycin		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/70 (0%)		0/24 (0%)
Serious Adverse Events
	Solithromycin		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/70 (1.4%)		1/24 (4.2%)
Infections and infestations
Pneumonia	1/70 (1.4%)	1	0/24 (0%)	0
Pneumonia Viral	0/70 (0%)	0	1/24 (4.2%)	1
Other (Not Including Serious) Adverse Events
	Solithromycin		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/70 (34.3%)		7/24 (29.2%)
Blood and lymphatic system disorders
Anaemia	1/70 (1.4%)	1	0/24 (0%)	0
Cardiac disorders
Bradycardia	0/70 (0%)	0	1/24 (4.2%)	1
Gastrointestinal disorders
Diarrhoea	1/70 (1.4%)	1	4/24 (16.7%)	4
Abdominal Discomfort	1/70 (1.4%)	1	0/24 (0%)	0
Vomiting	1/70 (1.4%)	1	0/24 (0%)	0
General disorders
Fatigue	0/70 (0%)	0	1/24 (4.2%)	1
Infusion Site Pain	6/70 (8.6%)	6	0/24 (0%)	0
Infusion Site Pruritus	1/70 (1.4%)	1	0/24 (0%)	0
Infusion Site Urticaria	1/70 (1.4%)	1	0/24 (0%)	0
Injection Site Reaction	1/70 (1.4%)	1	0/24 (0%)	0
Oedema Peripheral	1/70 (1.4%)	1	0/24 (0%)	0
Infections and infestations
Bacteraemia	1/70 (1.4%)	1	0/24 (0%)	0
Infectious Pleural Effusion	1/70 (1.4%)	1	0/24 (0%)	0
Investigations
Alanine Aminotransferase Increased	3/70 (4.3%)	3	0/24 (0%)	0
Hepatic Enzyme Increased	1/70 (1.4%)	1	0/24 (0%)	0
Oxygen Saturation Decreased	1/70 (1.4%)	1	0/24 (0%)	0
Transaminases Increased	1/70 (1.4%)	1	0/24 (0%)	0
Metabolism and nutrition disorders
Hypokalaemia	0/70 (0%)	0	1/24 (4.2%)	1
Hyperglycaemia	1/70 (1.4%)	1	0/24 (0%)	0
Respiratory, thoracic and mediastinal disorders
Nasal Congestion	0/70 (0%)	0	1/24 (4.2%)	1
Epistaxis	1/70 (1.4%)	1	0/24 (0%)	0
Rhinitis Allergic	1/70 (1.4%)	1	0/24 (0%)	0
Tachypnoea	1/70 (1.4%)	1	0/24 (0%)	0
Skin and subcutaneous tissue disorders
Pruritus	1/70 (1.4%)	1	0/24 (0%)	0
Rash	1/70 (1.4%)	1	0/24 (0%)	0
Rash Erythematous	1/70 (1.4%)	1	0/24 (0%)	0
Rash Maculo-Papular	1/70 (1.4%)	1	0/24 (0%)	0
Urticaria	1/70 (1.4%)	1	0/24 (0%)	0
Vascular disorders
Phlebitis	5/70 (7.1%)	5	0/24 (0%)	0

Limitations/Caveats

The study was discontinued early due to a company business decision. Study discontinuation was not related to safety or tolerability.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Study Site will not submit its results for independent publication until after a coordinated, multicenter Study publication has been submitted or one (1) year after the conclusion of the Study, whichever occurs first. Study Site and/or Investigator shall submit any proposed publication or presentation resulting from Study Site's performance of the Protocol to the Prime Recipient for review and comment at least forty-five (45) days prior to the date of submission.