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Clinical Trial Results:
A randomized, placebo-controlled, double-blind, multi-center trial to assess the disease-modifying potential of transdermal nicotine in early Parkinson's disease in Germany and the USA (NIC-PD)

Summary
EudraCT number	2010-020299-42
Trial protocol	DE
Global end of trial date	15 Feb 2017

Results information
Results version number	v1(current)
This version publication date	23 Mar 2022
First version publication date	23 Mar 2022
Other versions
Summary report(s)	E3-Synopse_NIC-PD_V02F

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

KKS-135

ISRCTN number

US NCT number

NCT01560754

WHO universal trial number (UTN)

Sponsor organisation name

Philipps-Universität Marburg

Sponsor organisation address

Biegenstr. 10, Marburg, Germany, 35037

Public contact

KKS Marburg, Koordinierungszentrum für Klinische Studien, info@kks.uni-marburg.de

Scientific contact

KKS Marburg, Koordinierungszentrum für Klinische Studien, info@kks.uni-marburg.de

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

15 Feb 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

15 Feb 2017

Global end of trial reached?

Yes

Global end of trial date

15 Feb 2017

Was the trial ended prematurely?

Main objective of the trial

This study assessed the disease-modifying potential of transdermal nicotine treatment compared to placebo in early Parkinson’s disease (PD) patients over a treatment period of 12 months treatment plus 2 months wash-out: The primary endpoint reflecting the explanatory character of the trial was calculated as the difference between the nicotine arm and the placebo arm in the change in total UPDRS I-III score between baseline and 14 months (12 months treatment plus 2 months wash-out). The difference between the nicotine arm and the placebo arm in the change in total UPDRS I-III score between baseline and 12 months became a variant of the primary endpoint for pragmatic interpretation which is subordinated in this phase II trial.

Protection of trial subjects

None

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Aug 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 102

Country: Number of subjects enrolled

United States: 60

Worldwide total number of subjects

162

EEA total number of subjects

102

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants were recruited between period - between 17Oct2012 and 09Jul2015 with “last patient out” on 15Sept2016 with 163 subjects were randomized (61 at US centers, 102 at German centers) over a 33 months period. The progress through the phases of the trial is presented in the style of a CONSORT.

Screening details

Wash-out: The primary endpoint is calculated as the difference between the nicotine arm and the placebo arm in the change in total UPDRS I-III score between baseline and 60 weeks (14 months) (52 weeks treatment plus 8 weeks wash-out).

Period 1 title

overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

Patches, identical in size, shape and colour

Are arms mutually exclusive

Yes

Transdermal nicotine patch

Arm description

Transdermal nicotine patches (7 to 28 mg/day)

Arm type

Experimental

Investigational medicinal product name

NICOTINE

Investigational medicinal product code

N07B A01

Other name

SUB14645MIG

Pharmaceutical forms

Transdermal patch

Routes of administration

Transdermal use

Dosage and administration details

52 weeks treatment (7 to 28 mg/day) plus 3 weeks down-titration

Placebo patch

Arm description

Transdermal patches, identical in size, shape and colour

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Transdermal patch

Routes of administration

Transdermal use

Dosage and administration details

52 weeks treatment (7 to 28 mg/day) plus 3 weeks down-titration

Number of subjects in period 1	Transdermal nicotine patch	Placebo patch
Started	79	83
Completed	66	76
Not completed	13	7
end of study therapy	7	1
no valid assessment	6	6

Baseline characteristics

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Reporting group title

Transdermal nicotine patch

Reporting group description

Transdermal nicotine patches (7 to 28 mg/day)

Reporting group title

Placebo patch

Reporting group description

Transdermal patches, identical in size, shape and colour

Reporting group values	Transdermal nicotine patch	Placebo patch	Total
Number of subjects	79	83	162
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
geometric mean (standard deviation)	61 ( 9.5 )	61 ( 10.3 )	-
Gender categorical
Units: Subjects
Female	28	23	51
Male	51	60	111

End points

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Reporting group title

Transdermal nicotine patch

Reporting group description

Transdermal nicotine patches (7 to 28 mg/day)

Reporting group title

Placebo patch

Reporting group description

Transdermal patches, identical in size, shape and colour

Primary: Mean worsening of total UPDRS I-III score after 60 weeks (between baseline and 14 months; 12 months treatment plus 2 months wash-out)

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End point title

Mean worsening of total UPDRS I-III score after 60 weeks (between baseline and 14 months; 12 months treatment plus 2 months wash-out)

End point description

To demonstrate that transdermal nicotine treatment retrads disease progression as measured by change in total (part I,II, III) UPDRS score between baseline and after 52 weeks of study treatment plus two more months wash out (60 weeks)

End point type

Primary

End point timeframe

Baseline (T0), after 28 weeks (V6), after 40 weeks (V7), after 52 weeks (V8), after 55 weeks (V9), after 57 weeks (V10), after 60 weeks (V11)

End point values	Transdermal nicotine patch	Placebo patch
Number of subjects analysed	47	54
Units: Number
number (not applicable)	6.02	3.5

Stratified two-sided Mann-Whitney-Wilcoxon-test

Comparison groups

Transdermal nicotine patch v Placebo patch

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.056

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Point estimate

-3

Confidence interval

level

80%

sides

2-sided

lower limit

-6

upper limit

Variability estimate

Standard deviation

Adverse events

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Timeframe for reporting adverse events

Adverse events reporting period is defined from the time the informed consent is signed, up to and including 30 days following last administration of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Transdermal nicotine patch

Reporting group description

Transdermal nicotine patches (7 to 28 mg/day)

Reporting group title

Placebo patch

Reporting group description

Transdermal patches, identical in size, shape and colour

Serious adverse events	Transdermal nicotine patch	Placebo patch
Total subjects affected by serious adverse events
subjects affected / exposed	14 / 79 (17.72%)	7 / 83 (8.43%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	1 / 79 (1.27%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Catheterisation cardiac
subjects affected / exposed	0 / 79 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Pulmonary embolism
subjects affected / exposed	1 / 79 (1.27%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 79 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Varicose vein
subjects affected / exposed	1 / 79 (1.27%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Angina unstable
subjects affected / exposed	2 / 79 (2.53%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	2 / 79 (2.53%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 79 (1.27%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Cancer surgery
subjects affected / exposed	1 / 79 (1.27%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Knee arthroplasty
subjects affected / exposed	1 / 79 (1.27%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pituitary tumour removal
subjects affected / exposed	0 / 79 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Motor dysfunction
subjects affected / exposed	1 / 79 (1.27%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Parkinsonism
subjects affected / exposed	1 / 79 (1.27%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diplopia
subjects affected / exposed	0 / 79 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Orthostatic intolerance
subjects affected / exposed	1 / 79 (1.27%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Facial paresis
subjects affected / exposed	1 / 79 (1.27%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Waldenstrom's macroglobulinaemia recurrent
subjects affected / exposed	0 / 79 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Uterine haemorrhage
subjects affected / exposed	0 / 79 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	1 / 79 (1.27%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anxiety
subjects affected / exposed	0 / 79 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Bladder mass
subjects affected / exposed	1 / 79 (1.27%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Obstructive uropathy
subjects affected / exposed	1 / 79 (1.27%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Cervical spinal stenosis
subjects affected / exposed	1 / 79 (1.27%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 79 (1.27%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	1 / 79 (1.27%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Transdermal nicotine patch	Placebo patch
Total subjects affected by non serious adverse events
subjects affected / exposed	61 / 79 (77.22%)	69 / 83 (83.13%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	1 / 79 (1.27%)	4 / 83 (4.82%)
occurrences all number	1	4
Investigations
Weight decreased
subjects affected / exposed	4 / 79 (5.06%)	0 / 83 (0.00%)
occurrences all number	4	0
Vascular disorders
Hypertension
subjects affected / exposed	3 / 79 (3.80%)	5 / 83 (6.02%)
occurrences all number	3	5
Cardiac disorders
Dizziness
subjects affected / exposed	18 / 79 (22.78%)	12 / 83 (14.46%)
occurrences all number	28	14
Nervous system disorders
Motor dysfunction
subjects affected / exposed	1 / 79 (1.27%)	4 / 83 (4.82%)
occurrences all number	2	4
Headache
subjects affected / exposed	17 / 79 (21.52%)	15 / 83 (18.07%)
occurrences all number	23	23
Tremor
subjects affected / exposed	7 / 79 (8.86%)	6 / 83 (7.23%)
occurrences all number	9	6
Abnormal dreams
subjects affected / exposed	4 / 79 (5.06%)	1 / 83 (1.20%)
occurrences all number	6	2
General disorders and administration site conditions
Application site erythema
subjects affected / exposed	22 / 79 (27.85%)	14 / 83 (16.87%)
occurrences all number	29	19
Application site pruritus
subjects affected / exposed	8 / 79 (10.13%)	7 / 83 (8.43%)
occurrences all number	9	7
Application site reaction
subjects affected / exposed	1 / 79 (1.27%)	4 / 83 (4.82%)
occurrences all number	1	4
Fatigue
subjects affected / exposed	7 / 79 (8.86%)	2 / 83 (2.41%)
occurrences all number	10	3
Application site irritation
subjects affected / exposed	7 / 79 (8.86%)	2 / 83 (2.41%)
occurrences all number	7	2
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	4 / 79 (5.06%)	1 / 83 (1.20%)
occurrences all number	5	2
Gastrointestinal disorders
Nausea
subjects affected / exposed	10 / 79 (12.66%)	4 / 83 (4.82%)
occurrences all number	17	5
Constipation
subjects affected / exposed	5 / 79 (6.33%)	2 / 83 (2.41%)
occurrences all number	10	2
Vomiting
subjects affected / exposed	4 / 79 (5.06%)	1 / 83 (1.20%)
occurrences all number	5	2
Respiratory, thoracic and mediastinal disorders
Nasopharyngitis
subjects affected / exposed	13 / 79 (16.46%)	18 / 83 (21.69%)
occurrences all number	16	22
Upper respiratory tract infection
subjects affected / exposed	2 / 79 (2.53%)	4 / 83 (4.82%)
occurrences all number	2	5
Bronchitis
subjects affected / exposed	1 / 79 (1.27%)	4 / 83 (4.82%)
occurrences all number	1	4
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	12 / 79 (15.19%)	6 / 83 (7.23%)
occurrences all number	13	12
Skin reaction
subjects affected / exposed	6 / 79 (7.59%)	6 / 83 (7.23%)
occurrences all number	10	7
Rash
subjects affected / exposed	4 / 79 (5.06%)	4 / 83 (4.82%)
occurrences all number	5	4
Pruritus
subjects affected / exposed	6 / 79 (7.59%)	3 / 83 (3.61%)
occurrences all number	7	3
Dermatitis allergic
subjects affected / exposed	6 / 79 (7.59%)	2 / 83 (2.41%)
occurrences all number	6	3
Psychiatric disorders
Depression
subjects affected / exposed	2 / 79 (2.53%)	6 / 83 (7.23%)
occurrences all number	2	6
Insomnia
subjects affected / exposed	6 / 79 (7.59%)	6 / 83 (7.23%)
occurrences all number	6	6
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 79 (2.53%)	10 / 83 (12.05%)
occurrences all number	2	11
Musculoskeletal pain
subjects affected / exposed	3 / 79 (3.80%)	6 / 83 (7.23%)
occurrences all number	3	7
Pain in extremity
subjects affected / exposed	1 / 79 (1.27%)	7 / 83 (8.43%)
occurrences all number	1	7
Muscle spasms
subjects affected / exposed	1 / 79 (1.27%)	4 / 83 (4.82%)
occurrences all number	1	4

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A randomized, placebo-controlled, double-blind, multi-center trial to assess the disease-modifying potential of transdermal nicotine in early Parkinson's disease in Germany and the USA (NIC-PD)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Mean worsening of total UPDRS I-III score after 60 weeks (between baseline and 14 months; 12 months treatment plus 2 months wash-out)

Primary: Mean worsening of total UPDRS I-III score after 60 weeks (between baseline and 14 months; 12 months treatment plus 2 months wash-out)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A randomized, placebo-controlled, double-blind, multi-center trial to assess the disease-modifying potential of transdermal nicotine in early Parkinson's disease in Germany and the USA (NIC-PD)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Mean worsening of total UPDRS I-III score after 60 weeks (between baseline and 14 months; 12 months treatment plus 2 months wash-out)

Primary: Mean worsening of total UPDRS I-III score after 60 weeks (between baseline and 14 months; 12 months treatment plus 2 months wash-out)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A randomized, placebo-controlled, double-blind, multi-center trial to assess the disease-modifying potential of transdermal nicotine in early Parkinson's disease in Germany and the USA (NIC-PD)