MNK6106 for Liver Disease (Hepatic Cirrhosis) That in the Past Has Affected the Brain (Hepatic Encephalopathy)

• Sponsor: Mallinckrodt (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03712280
• Collaborator: (none)
• Enrollment: 50
• Locations: 5
• Arms: 4
• Actual Duration (Months): 19.4
• Patients Per Site: 10
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The main reason for this study is to see how the study drug interacts with the body.

It will compare different doses of the study drug with a drug already in use.

Participants will be adults with liver disease that has affected the brain in the past.

Condition or Disease	Intervention/Treatment	Phase
Hepatic Cirrhosis; Hepatic Encephalopathy (HE)	Drug: MNK6106; Drug: Rifaximin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-Label, Phase 2a Comparator Study to Assess the Pharmacodynamics, Safety and Pharmacokinetics of Oral Administration MNK6106 (L-Ornithine Phenylacetate) Versus Rifaximin in Subjects With Hepatic Cirrhosis and a History of Prior Episodes of Hepatic Encephalopathy
• Actual Study Start Date: Dec 1, 2018
• Actual Primary Completion Date: Jul 14, 2020
• Actual Study Completion Date: Jul 14, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A: MNK6106 2 grams (tid) Participants receive 2 tablets of MNK6106 three times daily (tid) for 5 days	Drug: MNK6106; 1 gram tablet of MNK6106 for oral administration; Other Names: Study Drug L-Ornithine Phenylacetate
Experimental: Group B: MNK6106 4 grams (bid) Participants receive 4 tablets of MNK6106 twice daily (bid) for 5 days	Drug: MNK6106; 1 gram tablet of MNK6106 for oral administration; Other Names: Study Drug L-Ornithine Phenylacetate
Experimental: Group C: MNK6106 4 grams (tid) Participants receive 4 tablets of MNK6106 tid for 5 days	Drug: MNK6106; 1 gram tablet of MNK6106 for oral administration; Other Names: Study Drug L-Ornithine Phenylacetate
Active Comparator: Group D: Rifaximin 550 mg (bid) Participants receive 1 tablet of rifaximin bid for 5 days	Drug: Rifaximin; 550 mg tablet of rifaximin for oral administration; Other Names: Xifaxan

Outcome Measures

Primary Outcome Measures

1. Ammonia Plasma Levels at Baseline and Day 5 [Baseline, Day 5]

   This test measures the level of ammonia in your blood. Ammonia, also known as NH3, is a waste product made by your body during the digestion of protein. Normally, ammonia is processed in the liver, where it is changed into another waste product called urea. Urea is passed from the body in urine. If your body cannot process or eliminate ammonia, a lab test of a blood sample shows it has built up in the bloodstream. High ammonia levels in the blood can lead to serious health problems, including hepatic encephalopathy.

Secondary Outcome Measures

1. Number of Participants With Adverse Events by the End of the Trial [within 15 days]

   End of trial is defined as 7 (+/-3) days after last study treatment

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

A potential participant may only be included if (at screening), he/she:

1. Understands the study and has signed informed consent

2. Is an adult, not pregnant or lactating

3. Has cirrhosis of the liver

4. Has had 1 instance of HE within 12 months

5. Has hyperammonaemia defined as ≥37 μmol/L at screening

Key Exclusion Criteria:

A potential participant will be excluded if (at screening), he/she:

1. Has contraindicated allergies

2. Expects liver transplant within 1 month

3. Has had a liver shunt within the last 3 months

4. Has inadequate kidney, gastrointestinal, or cardiac function

5. Has cancer, infection, lab abnormalities, or any other condition that, per protocol or in the opinion of the investigator might compromise:

6. the safety and well-being of the participant or potential offspring

7. the safety of study staff

8. the analysis of results

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Southern California Research Center	Coronado	California	United States	92118
2	Inland Empire Clinical Trials	Rialto	California	United States	92377
3	Global Clinical Professionals	Saint Petersburg	Florida	United States	33702
4	American Research Corporation at the Texas Liver Institute	San Antonio	Texas	United States	78215
5	Fundacion de Investigacion (Research Foundation)	San Juan		Puerto Rico	00927

Sponsors and Collaborators

• Mallinckrodt

Investigators

• Study Director: Clinical Team Leader, Mallinckrodt

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 21, 2020

More Information

Publications

None provided.

• Responsible Party: Mallinckrodt
• ClinicalTrials.gov Identifier: NCT03712280
• Other Study ID Numbers: MNK61062107
• First Posted: Oct 19, 2018
• Last Update Posted: Jul 20, 2021
• Last Verified: Jun 1, 2021

• 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
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Liver Cirrhosis; Hepatic Encephalopathy; Brain Diseases; Fibrosis; Rifaximin; Phenylacetic acid

Study Results

Participant Flow

Recruitment Details	All 50 participants were enrolled in the United States and Puerto Rico

Arm/Group Title	Group A: MNK6106 2 Grams (Tid)	Group B: MNK6106 4 Grams (Bid)	Group C: MNK6106 4 Grams (Tid)	Group D: Rifaximin 550 mg (Bid)
Arm/Group Description	Participants receive 2 (1 gm) tablets of MNK6106 three times daily (tid) for 5 days	Participants receive 4 (1 gm) tablets of MNK6106 twice daily (bid) for 5 days	Participants receive 4 (1 gm) tablets of MNK6106 tid for 5 days	Participants receive 1 (500 mg) tablet of rifaximin bid for 5 days
Period Title: Overall Study
STARTED	12	12	13	13
Safety Population	12	11	13	12
Modified Intent to Treat Population	12	11	13	12
Completed 5 Day Treatment	11	11	12	12
COMPLETED	11	11	12	12
NOT COMPLETED	1	1	1	1

Baseline Characteristics

Arm/Group Title	Group A: MNK6106 2 Grams (Tid)	Group B: MNK6106 4 Grams (Bid)	Group C: MNK6106 4 Grams (Tid)	Group D: Rifaximin 550 mg (Bid)	Total
Arm/Group Description	Participants receive 2 (1 gm) tablets of MNK6106 three times daily (tid) for 5 days	Participants receive 4 (1 gm) tablets of MNK6106 twice daily (bid) for 5 days	Participants receive 4 (1 gm) tablets of MNK6106 tid for 5 days	Participants receive 1 (500 mg) tablet of rifaximin bid for 5 days	Total of all reporting groups
Overall Participants	12	11	13	12	48
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	11 91.7%	10 90.9%	10 76.9%	11 91.7%	42 87.5%
>=65 years	1 8.3%	1 9.1%	3 23.1%	1 8.3%	6 12.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.2 (8.10)	58.2 (7.95)	58.2 (10.56)	55.2 (9.09)	57.2 (8.84)
Sex: Female, Male (Count of Participants)
Female	6 50%	3 27.3%	5 38.5%	6 50%	20 41.7%
Male	6 50%	8 72.7%	8 61.5%	6 50%	28 58.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	11 91.7%	7 63.6%	7 53.8%	10 83.3%	35 72.9%
Not Hispanic or Latino	1 8.3%	4 36.4%	6 46.2%	2 16.7%	13 27.1%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	1 7.7%	0 0%	1 2.1%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	2 16.7%	0 0%	0 0%	1 8.3%	3 6.3%
White	10 83.3%	11 100%	11 84.6%	11 91.7%	43 89.6%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	1 7.7%	0 0%	1 2.1%
Region of Enrollment (participants) [Number]
United States	12 100%	11 100%	13 100%	12 100%	48 100%

Outcome Measures

1. Primary Outcome

Title	Ammonia Plasma Levels at Baseline and Day 5
Description	This test measures the level of ammonia in your blood. Ammonia, also known as NH3, is a waste product made by your body during the digestion of protein. Normally, ammonia is processed in the liver, where it is changed into another waste product called urea. Urea is passed from the body in urine. If your body cannot process or eliminate ammonia, a lab test of a blood sample shows it has built up in the bloodstream. High ammonia levels in the blood can lead to serious health problems, including hepatic encephalopathy.
Time Frame	Baseline, Day 5

Outcome Measure Data

Analysis Population Description

modified Intent to Treat (mITT)

Arm/Group Title	Group A: MNK6106 2 Grams (Tid)	Group B: MNK6106 4 Grams (Bid)	Group C: MNK6106 4 Grams (Tid)	Group D: Rifaximin 550 mg (Bid)
Arm/Group Description	Participants receive 2 (1 gm) tablets of MNK6106 three times daily (tid) for 5 days	Participants receive 4 (1 gm) tablets of MNK6106 twice daily (bid) for 5 days	Participants receive 4 (1 gm) tablets of MNK6106 tid for 5 days	Participants receive 1 (500 mg) tablet of rifaximin bid for 5 days
Measure Participants	12	11	13	12
Baseline	70.4 (23.4)	91.4 (35.0)	92.6 (34.7)	78.1 (25.0)
Day 5/Pre-Dose in the Morning	72.7 (21.8)	63.9 (16.9)	74.9 (21.9)	75.8 (31.3)
Day 5/4 Hours Post Morning Dose	69.8 (27.7)	60.9 (13.3)	73.0 (11.5)	71.6 (29.5)

2. Secondary Outcome

Title	Number of Participants With Adverse Events by the End of the Trial
Description	End of trial is defined as 7 (+/-3) days after last study treatment
Time Frame	within 15 days

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Group A: MNK6106 2 Grams (Tid)	Group B: MNK6106 4 Grams (Bid)	Group C: MNK6106 4 Grams (Tid)	Group D: Rifaximin 550 mg (Bid)
Arm/Group Description	Participants receive 2 (1 gm) tablets of MNK6106 three times daily (tid) for 5 days	Participants receive 4 (1 gm) tablets of MNK6106 twice daily (bid) for 5 days	Participants receive 4 (1 gm) tablets of MNK6106 tid for 5 days	Participants receive 1 (500 mg) tablet of rifaximin bid for 5 days
Measure Participants	12	11	13	12
Affected by Serious Adverse Events	0 0%	0 0%	2 15.4%	0 0%
Affected by Any Non-serious Adverse Event	5 41.7%	6 54.5%	9 69.2%	5 41.7%
Affected by Non-serious Adverse Events in the 5% Reporting Threshold	5 41.7%	6 54.5%	8 61.5%	5 41.7%

Adverse Events

Time Frame	within 15 days
Adverse Event Reporting Description	All serious adverse events are reported. Non-Serious Treatment-Emergent Adverse Events reported by 5% or more participants in any treatment group are reported.
Arm/Group Title	Group A: MNK6106 2 Grams (Tid)		Group B: MNK6106 4 Grams (Bid)		Group C: MNK6106 4 Grams (Tid)		Group D: Rifaximin 550 mg (Bid)
Arm/Group Description	Participants receive 2 (1 gm) tablets of MNK6106 three times daily (tid) for 5 days		Participants receive 4 (1 gm) tablets of MNK6106 twice daily (bid) for 5 days		Participants receive 4 (1 gm) tablets of MNK6106 tid for 5 days		Participants receive 1 (500 mg) tablet of rifaximin bid for 5 days
All Cause Mortality
	Group A: MNK6106 2 Grams (Tid)		Group B: MNK6106 4 Grams (Bid)		Group C: MNK6106 4 Grams (Tid)		Group D: Rifaximin 550 mg (Bid)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/11 (0%)		0/13 (0%)		0/12 (0%)
Serious Adverse Events
	Group A: MNK6106 2 Grams (Tid)		Group B: MNK6106 4 Grams (Bid)		Group C: MNK6106 4 Grams (Tid)		Group D: Rifaximin 550 mg (Bid)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/11 (0%)		2/13 (15.4%)		0/12 (0%)
Gastrointestinal disorders
Ascites	0/12 (0%)	0	0/11 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0
Haemorrhoidal haemorrhage	0/12 (0%)	0	0/11 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0
Metabolism and nutrition disorders
Hyponatraemia	0/12 (0%)	0	0/11 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0
Psychiatric disorders
Confusional state	0/12 (0%)	0	0/11 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0
Other (Not Including Serious) Adverse Events
	Group A: MNK6106 2 Grams (Tid)		Group B: MNK6106 4 Grams (Bid)		Group C: MNK6106 4 Grams (Tid)		Group D: Rifaximin 550 mg (Bid)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/12 (41.7%)		6/11 (54.5%)		8/13 (61.5%)		5/12 (41.7%)
Blood and lymphatic system disorders
Anaemia	1/12 (8.3%)	1	0/11 (0%)	0	0/13 (0%)	0	1/12 (8.3%)	1
Eye disorders
Vision blurred	1/12 (8.3%)	1	0/11 (0%)	0	0/13 (0%)	0	0/12 (0%)	0
Gastrointestinal disorders
Abdominal pain upper	0/12 (0%)	0	1/11 (9.1%)	1	1/13 (7.7%)	1	0/12 (0%)	0
Haemorrhoids	0/12 (0%)	0	0/11 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0
Nausea	1/12 (8.3%)	2	0/11 (0%)	0	2/13 (15.4%)	4	0/12 (0%)	0
Vomiting	2/12 (16.7%)	3	0/11 (0%)	0	2/13 (15.4%)	3	0/12 (0%)	0
General disorders
Chills	1/12 (8.3%)	1	0/11 (0%)	0	0/13 (0%)	0	0/12 (0%)	0
Fatigue	0/12 (0%)	0	1/11 (9.1%)	1	1/13 (7.7%)	1	0/12 (0%)	0
Oedema peripheral	0/12 (0%)	0	1/11 (9.1%)	1	0/13 (0%)	0	0/12 (0%)	0
Infections and infestations
Urinary tract infection	0/12 (0%)	0	0/11 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0
Investigations
Urine output decreased	0/12 (0%)	0	0/11 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/12 (8.3%)	1	0/11 (0%)	0	0/13 (0%)	0	0/12 (0%)	0
Hyperammonaemia	0/12 (0%)	0	0/11 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0
Hyperkalaemia	0/12 (0%)	0	0/11 (0%)	0	0/13 (0%)	0	1/12 (8.3%)	1
Hypocalcaemia	1/12 (8.3%)	1	0/11 (0%)	0	0/13 (0%)	0	0/12 (0%)	0
Hypokalaemia	0/12 (0%)	0	1/11 (9.1%)	1	0/13 (0%)	0	1/12 (8.3%)	1
Hypomagnesaemia	0/12 (0%)	0	0/11 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0
Vitamin D deficiency	0/12 (0%)	0	0/11 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0
Nervous system disorders
Dizziness	0/12 (0%)	0	0/11 (0%)	0	2/13 (15.4%)	2	1/12 (8.3%)	1
Headache	1/12 (8.3%)	1	0/11 (0%)	0	1/13 (7.7%)	1	1/12 (8.3%)	1
Hepatic encephalopathy	0/12 (0%)	0	0/11 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0
Tension headache	0/12 (0%)	0	0/11 (0%)	0	0/13 (0%)	0	1/12 (8.3%)	1
Tremor	0/12 (0%)	0	0/11 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0
Renal and urinary disorders
Azotaemia	0/12 (0%)	0	0/11 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0
Skin and subcutaneous tissue disorders
Rash	0/12 (0%)	0	0/11 (0%)	0	0/13 (0%)	0	1/12 (8.3%)	1
Vascular disorders
Hypotension	1/12 (8.3%)	1	2/11 (18.2%)	2	0/13 (0%)	0	2/12 (16.7%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.