Trial Outcomes & Findings for The Effect of Diflunisal on Familial Amyloidosis (NCT NCT00294671)

NCT ID: NCT00294671

Last Updated: 2017-03-17

Results Overview

The primary endpoint, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurologic deficits) to 270 points (no detectable peripheral nerve function).

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

130 participants

Primary outcome timeframe

Baseline, 1 and 2 years

Results posted on

2017-03-17

Participant Flow

Participants were recruited between May 2006 and December 2010 from amyloid centers of excellence in Sweden (Umea), Italy (Pavia), United Kingdom (London), Japan (Matsumoto and Kumamoto), and the United States (New York, Minnesota, and Massachusetts).

All enrolled participants were randomized to treatment groups.

Participant milestones

Participant milestones
Measure	Diflunisal Diflunisal 250 mg taken by mouth twice daily for 24 months	Placebo Placebo, an inactive substance, taken by mouth twice daily for 24 months
Overall Study STARTED	64	66
Overall Study COMPLETED	37	26
Overall Study NOT COMPLETED	27	40

Reasons for withdrawal

Reasons for withdrawal
Measure	Diflunisal Diflunisal 250 mg taken by mouth twice daily for 24 months	Placebo Placebo, an inactive substance, taken by mouth twice daily for 24 months
Overall Study Lack of Efficacy	11	23
Overall Study Liver transplant	7	9
Overall Study Drug related adverse event (AE)	4	2
Overall Study Non-drug related AE	3	2
Overall Study Lost to Follow-up	1	3
Overall Study Non-compliance	1	0
Overall Study Death	0	1

Baseline Characteristics

The Effect of Diflunisal on Familial Amyloidosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Diflunisal n=64 Participants Diflunisal 250 mg taken by mouth twice daily for 24 months	Placebo n=66 Participants Placebo, an inactive substance, taken by mouth twice daily for 24 months	Total n=130 Participants Total of all reporting groups
Age, Continuous	60.3 years STANDARD_DEVIATION 11.7 • n=99 Participants	59.2 years STANDARD_DEVIATION 12.2 • n=107 Participants	59.7 years STANDARD_DEVIATION 11.9 • n=206 Participants
Sex: Female, Male Female	21 Participants n=99 Participants	22 Participants n=107 Participants	43 Participants n=206 Participants
Sex: Female, Male Male	43 Participants n=99 Participants	44 Participants n=107 Participants	87 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Asian	8 Participants n=99 Participants	6 Participants n=107 Participants	14 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Black or African American	1 Participants n=99 Participants	5 Participants n=107 Participants	6 Participants n=206 Participants
Race (NIH/OMB) White	52 Participants n=99 Participants	50 Participants n=107 Participants	102 Participants n=206 Participants
Race (NIH/OMB) More than one race	3 Participants n=99 Participants	4 Participants n=107 Participants	7 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	1 Participants n=107 Participants	1 Participants n=206 Participants
Region of Enrollment United States	34 participants n=99 Participants	35 participants n=107 Participants	69 participants n=206 Participants
Region of Enrollment United Kingdom	3 participants n=99 Participants	4 participants n=107 Participants	7 participants n=206 Participants
Region of Enrollment Italy	10 participants n=99 Participants	11 participants n=107 Participants	21 participants n=206 Participants
Region of Enrollment Japan	5 participants n=99 Participants	4 participants n=107 Participants	9 participants n=206 Participants
Region of Enrollment Sweden	12 participants n=99 Participants	12 participants n=107 Participants	24 participants n=206 Participants
NIS+7 score	51.6 units on a scale STANDARD_DEVIATION 42.8 • n=99 Participants	59.0 units on a scale STANDARD_DEVIATION 50 • n=107 Participants	55.3 units on a scale STANDARD_DEVIATION 46.5 • n=206 Participants
Kumamoto score	15.3 units on a scale STANDARD_DEVIATION 10.8 • n=99 Participants	16.7 units on a scale STANDARD_DEVIATION 13.5 • n=107 Participants	16.0 units on a scale STANDARD_DEVIATION 12.2 • n=206 Participants
Modified BMI	1024.4 kg/M2 x g/L STANDARD_DEVIATION 226.3 • n=99 Participants	1019 kg/M2 x g/L STANDARD_DEVIATION 255 • n=107 Participants	1021.7 kg/M2 x g/L STANDARD_DEVIATION 240.4 • n=206 Participants
SF-36 physical component score	35.9 units on a scale STANDARD_DEVIATION 11.6 • n=99 Participants	34.8 units on a scale STANDARD_DEVIATION 11 • n=107 Participants	35.4 units on a scale STANDARD_DEVIATION 11.3 • n=206 Participants
SF-36 mental component score	46.6 units on a scale STANDARD_DEVIATION 14.1 • n=99 Participants	46.5 units on a scale STANDARD_DEVIATION 11.8 • n=107 Participants	46.6 units on a scale STANDARD_DEVIATION 12.9 • n=206 Participants

PRIMARY outcome

Timeframe: Baseline, 1 and 2 years

Population: Longitudinal analysis examined data from all 130 participants using intention-to-treat principles.

The primary endpoint, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurologic deficits) to 270 points (no detectable peripheral nerve function).

Outcome measures

Outcome measures
Measure	Diflunisal n=64 Participants Diflunisal 250 mg taken by mouth twice daily for 24 months	Placebo n=66 Participants Placebo, an inactive substance, taken by mouth twice daily for 24 months
Neurologic Impairment Score + 7 (NIS+7) Change from baseline to 2 years	8.2 units on a scale Interval 2.9 to 13.6	26.3 units on a scale Interval 20.2 to 32.4
Neurologic Impairment Score + 7 (NIS+7) Change from baseline to 1 year	6.2 units on a scale Interval 2.8 to 9.6	12.5 units on a scale Interval 8.6 to 16.4

SECONDARY outcome

Timeframe: Baseline, 1 and 2 years

Change from baseline of the Kumamoto Score (0-102 points, increasing with disease severity), a clinical neurologic scale of motor, sensory, and autonomic function combined with heart and kidney end organ measures developed to track disease progression in Familial Amyloid Polyneuropathy (ATTR-FAP)

Outcome measures

Outcome measures
Measure	Diflunisal n=64 Participants Diflunisal 250 mg taken by mouth twice daily for 24 months	Placebo n=66 Participants Placebo, an inactive substance, taken by mouth twice daily for 24 months
Kumamoto Neurologic Scale; Change from baseline to 2 years	3.1 units on a scale Interval 1.1 to 5.1	8.0 units on a scale Interval 5.8 to 10.3
Kumamoto Neurologic Scale; Change from baseline to 1 year	1.9 units on a scale Interval 0.1 to 3.7	4.1 units on a scale Interval 2.1 to 6.2

SECONDARY outcome

Timeframe: Baseline, 1 and 2 years

The product of body mass index (BMI) and serum albumin level (g/L) \[kg/M2xg/L\].

Outcome measures

Outcome measures
Measure	Diflunisal n=64 Participants Diflunisal 250 mg taken by mouth twice daily for 24 months	Placebo n=66 Participants Placebo, an inactive substance, taken by mouth twice daily for 24 months
Modified Body Mass Index (mBMI); Change from baseline to 2 years	-33.7 kg/M2xg/L Interval -69.3 to 1.8	-67.9 kg/M2xg/L Interval -108.1 to -27.7
Modified Body Mass Index (mBMI); Change from baseline to 1 year	-18.7 kg/M2xg/L Interval -51.6 to 14.1	-38.5 kg/M2xg/L Interval -74.9 to -2.1

SECONDARY outcome

Timeframe: Baseline, 1 and 2 years

Population: Longitudinal analysis examined data from all 130 participants using intention-to-treat principles.

The 36 item short-form health survey (SF-36) was used to assess the difference between treatment groups for change of physical component scores over 2 years treatment. Range 0-100; lower scores reflect lower quality-of-life.

Outcome measures

Outcome measures
Measure	Diflunisal n=64 Participants Diflunisal 250 mg taken by mouth twice daily for 24 months	Placebo n=66 Participants Placebo, an inactive substance, taken by mouth twice daily for 24 months
Quality of Life Questionnaire: SF-36 Physical Component Score Change from baseline to 2 years	1.2 units on a scale Interval -1.2 to 3.7	-4.9 units on a scale Interval -7.6 to -2.1
Quality of Life Questionnaire: SF-36 Physical Component Score Change from baseline to 1 year	0.7 units on a scale Interval -1.1 to 2.5	-1.9 units on a scale Interval -3.9 to 0.2

SECONDARY outcome

Timeframe: Baseline, 1 and 2 years

The 36 item short-form health survey (SF-36) was used to assess the difference between treatment groups for change of mental component scores over 2 years treatment. Range 0-100; lower scores reflect lower quality-of-life.

Outcome measures

Outcome measures
Measure	Diflunisal n=64 Participants Diflunisal 250 mg taken by mouth twice daily for 24 months	Placebo n=66 Participants Placebo, an inactive substance, taken by mouth twice daily for 24 months
Quality of Life Questionnaire: SF-36 Mental Component Score Change from baseline to 2 years	3.5 units on a scale Interval 0.4 to 6.7	-0.9 units on a scale Interval -4.4 to 2.5
Quality of Life Questionnaire: SF-36 Mental Component Score Change from baseline to 1 year	2.5 units on a scale Interval 0.0 to 5.1	0.8 units on a scale Interval -2.0 to 3.6

Adverse Events

Diflunisal

Serious events: 3 serious events

Other events: 29 other events

Deaths: 0 deaths

Placebo

Serious events: 4 serious events

Other events: 27 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Diflunisal n=64 participants at risk Diflunisal 250 mg taken by mouth twice daily for 24 months	Placebo n=66 participants at risk Placebo, an inactive substance, taken by mouth twice daily for 24 months
Gastrointestinal disorders Gastrointestinal disorders	1.6% 1/64 • Number of events 3 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	3.0% 2/66 • Number of events 3 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Infections and infestations Infections and infestations	0.00% 0/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	1.5% 1/66 • Number of events 1 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Cardiac disorders Cardiac disorders	3.1% 2/64 • Number of events 2 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	1.5% 1/66 • Number of events 2 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Injury, poisoning and procedural complications Injury, poisoning and procedural complications	1.6% 1/64 • Number of events 1 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	0.00% 0/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Renal and urinary disorders Renal and urinary disorders	0.00% 0/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	3.0% 2/66 • Number of events 2 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.

Other adverse events

Other adverse events
Measure	Diflunisal n=64 participants at risk Diflunisal 250 mg taken by mouth twice daily for 24 months	Placebo n=66 participants at risk Placebo, an inactive substance, taken by mouth twice daily for 24 months
Infections and infestations Infections	37.5% 24/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	40.9% 27/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Gastrointestinal disorders GI disorders	35.9% 23/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	37.9% 25/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Nervous system disorders Nervous system disorders	35.9% 23/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	30.3% 20/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders	29.7% 19/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	12.1% 8/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
General disorders General disorders	29.7% 19/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	10.6% 7/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Cardiac disorders Cardiac disorders	23.4% 15/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	13.6% 9/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Respiratory, thoracic and mediastinal disorders Respiratory disorders	18.8% 12/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	16.7% 11/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Injury, poisoning and procedural complications Injury, poisoning and procedural complications	20.3% 13/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	13.6% 9/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Investigations Investigations	17.2% 11/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	16.7% 11/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Renal and urinary disorders Renal and urinary disorders	15.6% 10/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	18.2% 12/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Vascular disorders Vascular disorders	17.2% 11/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	10.6% 7/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Eye disorders Eye disorders	12.5% 8/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	13.6% 9/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Metabolism and nutrition disorders Metabolism and nutrition disorders	6.2% 4/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	13.6% 9/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Psychiatric disorders Psychiatric disorders	7.8% 5/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	10.6% 7/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders	9.4% 6/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	9.1% 6/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Surgical and medical procedures Surgical and medical procedures	7.8% 5/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	4.5% 3/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Blood and lymphatic system disorders Blood and lymphatic system disorders	1.6% 1/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	4.5% 3/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms	3.1% 2/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	1.5% 1/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Ear and labyrinth disorders Ear and labyrinth disorders	1.6% 1/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	1.5% 1/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Endocrine disorders Endocrine disorders	1.6% 1/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	0.00% 0/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Hepatobiliary disorders Hepatobiliary disorders	1.6% 1/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	0.00% 0/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Immune system disorders Immune system disorders	1.6% 1/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	0.00% 0/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.
Reproductive system and breast disorders Reproductive system and breast disorders	1.6% 1/64 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.	0.00% 0/66 • Adverse event data were collected for 2 years or until study withdrawal. Adverse events were collected and analyzed by affected organ system.

Additional Information

Dr. John L. Berk

Amyloidosis Center, Boston Medical Center

Phone: 617-638-4494

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place