US 2011 0118227A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0118227 A1 White et al. (43) Pub. Date: May 19, 2011 (54) METHODS FOR THE TREATMENT OF Pat. No. 7,799.769, which is a continuation of appli FBROMYALGA AND CHRONIC EATGUE cation No. 10/464,310, filed on Jun. 18, 2003, now SYNDROME abandoned. (75) Inventors: Hillary D. White, S. Pomfret, VT Publication Classification (US); Robert Gyurik, Exeter, NH (51) Int. Cl. (US) A6II 3/568 (2006.01) A6IP 29/00 (2006.01) (73) Assignee: White Mountain Pharma, Inc., A6IP5/26 (2006.01) New York, NY (US) GOIN 33/74. (2006.01) (21) Appl. No.: 12/949,644 (52) U.S. Cl. ........................................ 514/179; 435/7.92 (22) Filed: Nov. 18, 2010 (57) ABSTRACT The invention relates to methods for the treatment of fibro Related U.S. Application Data myalgia and chronic fatigue syndrome by administration of a (63) Continuation-in-part of application No. 12/837,310, transdermally applied androgen composition. The treatment filed on Jul. 15, 2010, which is a continuation of appli is both safe and effective for treating fibromyalgia-related cation No. 11/303,813, filed on Dec. 16, 2005, now pain and fatigue, as well as chronic fatigue syndrome. Patent Application Publication May 19, 2011 Sheet 1 of 33 US 2011/O118227 A1 A Total Testosterone Day 1 3.5 - - FG. A ME OF DAY 35 Awamwawraarvavarawawawasawawawawawayawawawasawa-ra-Mawraa-raB. Total Testosterone Day 28 F.G. B. e & o c. c. o c. Co 9 S S S E & & -e-07 TME OF DAY -o-018 C, Tota Testosteroie d1(circles), d28(squares), Meant SE, n=12 3.5 fore F.G. C TMEO DAY Patent Application Publication May 19, 2011 Sheet 2 of 33 US 2011/0118227 A1 8 A. Free Testosterone Day 1 7 6 - 5 54O) - H - - - - - - - - - - - - - - - - - - - - -1- - - - - - - FIG. 2A S3 H-2 22 Seetzssesses ll. 1 O - A . C C C C C C Cld Cd O cad O CO d o Cld C C C C C C CD O O. O. O. d O cos co s () is cd do o d\ c ( s. co do wns w- v- w w CN CN 8 7 6 5 - S 4 FIG. 2B 2 3 St - * - 1 O - 53(O CO So SCr Sw S() SCO &C 3N C CN S (O CO --e-018, - - - - v - re- (N on C. Free Testosterone 5 d1 (circles), d28(squares) Mean it SE 4 33 E FIG. 2C 22 St 1 Patent Application Publication US 2011/O118227 A1 ?:?********************************* Tender Point (SEM) FIG. 4 Patent Application Publication May 19, 2011 Sheet 5 of 33 US 2011/O118227 A1 A. P Walue Muscle Pain Fe OO1 Stiffness m I O.04 Fatigue upon Day 1 awakening O Day 28 - FIG. 5A Libido OOO2 O 2 4 6 8 1O B. PValue Day 1 D Day 28 FIG.SB WAS SCale Patent Application Publication May 19, 2011 Sheet 6 of 33 US 2011/0118227 A1 Subject 1 Time (hr) -- T Day 0 -C-T Day 28 - - A - - Fi Day 0 - - -X Ff Day 28 FIG. 6A Subject 2 Time (hr) --Ti Day 0 -O-T. Day 28 - - - A -- F Day 0 - - -x FTDay 28 F.G. 6B Patent Application Publication May 19, 2011 Sheet 7 of 33 US 2011/0118227 A1 Subject 3 Time (hr) -- Day 0 - - TT Day 28 - - -A - FTDay 0 - - -x -- FT Day 28 F.G. 6C 5 4.5 Y -E 4 -5 g 3.5 3. 5 3 3 is 2.5 s 1.5 s CX C - 0.5 U Time (hi) --T T Day 0 -O-T. Day 28 - - - A -- FT Day 0 - - -K - - Ft Day 28 F.G. 6D Patent Application Publication May 19, 2011 Sheet 8 of 33 US 2011/O118227 A1 Subject 6 1. S. S S. g 3 S D C O C O c time (h) --T Day 0 ---TDay 28 - - A - - F Day 0 - - -x - - FDay 28 F.G. 6E Subject 7 8 8 7 2K - - - - - - - - - - - - ........ 7 A -X ...? a S 6 xe, KYK ---. &: 6 S a , s A. d 5 A, A. s S. 5 X, as 3 4. ASA - A SE 4 s St A. * ES st is 3 ar 3 S. 8 2 --- 28 c 1 - 1st -0-0--has is reo. 1 1 , O 5 10 15 2O 25 Time (hr) --TT Day () --TDay 28 - - -A - - Fi Day 0 - - -x - - F Day 28 F.G. 6F Patent Application Publication May 19, 2011 Sheet 9 of 33 US 2011/O118227 A1 Subject 8 Time (hr) --Ti Day 0 ---TT Day 28 - - - A -- FTDay 0 - - -X - F Day 28 FIG. 6G Subject 9 3.5 - -axis O O 3.5 ar 3 3 1. K. g 2.5 K w X X -ca 2.5 3. MN K - Y - - - - - - - - . es5 2 A- As& thr-A-sist ' ' ' ' . <-2 5 re-Kg2/ is SS----A --see--- a-- 1.5 gE - A. ------ m --rocor-ra------ar-r-r- 1 OO ru8. " is Cd 0.5i t- orroo ar 0.5 - r A o re- - O 5 Q 15 2 25 Time (hr) -- TT Day O -O-TT Day 28 - - -A - - Ft Day 0 - - -x - Ft Day 28 F.G. 6H Patent Application Publication May 19, 2011 Sheet 10 of 33 US 2011/O118227 A1 Subject 10 Time (hr) --Ti Day O --TDay 28 - - - A - - Ft Day ( - - -K - - F Day 28 F.G. 6 Subject 11 Time (hr) -- T Day O --Ti Day 28 - - A - FTDay 0 - - x - F Day 28 FG, 6. Patent Application Publication May 19, 2011 Sheet 11 of 33 US 2011/O118227 A1 Subject 12 Time (hr) -- Day 0 -O-T. Day 28 - - - A - - FTDay 0 - - x - FTDay 28 F.G. 6K Subject 13 3, 5 time (hr) -- Day O -- i r Day 28 - - -A - - FTDay 0 - - -k FTDay 28 F.G. 6 Patent Application Publication May 19, 2011 Sheet 12 of 33 US 2011/O118227 A1 Wear Walues with Confidence intervals 2 5 Cmin, Cmin, Day 1 Day 28 F.G. 6M W Patent Application Publication May 19, 2011 Sheet 13 of 33 US 2011/O118227 A1 Fibromyalgia Study, Preliminary Patient Questionnaire Name: Age. Date of birth: SS# Address: If you are enrolled in this study, your address and social security number are required for lS to pay you. Daytime Telephone Number: Patient code: Yes No Please the laterior the is a How tall are you? How many pounds do you weigh? Have you been diagnosed with Fibromyalgia Syndrome? urrrm Do you have widespread pain all over? (above/below waist, right/left sides) Are you frequently fatigued? Have you had your ovaries removed? lf yes, please give the date of your Surgery Are you on hormone therapy? If yes, what hormones: Are you willing to discontinue your hormone therapy for 6 months? When was your last menstrual period? Do you have undiagnosed vaginal bleeding? Do you Smoke? If yes, how many cigarettes a day? Do you drink alcohol? If yes, how much a day, a week? Do you have high blood pressure, cardiovascular disease, liver or kidney disease, cancer, diabetes? Specify: Do you have any skin diseases? Specify: Do you take St. John’s wort, ginger root, antidepressants? If yes, are you willing to stop taking them for 6 months? | Are you willing to exercise 20 minutes a day, 5 days a week? Thank you for answering this questionnaire. You may explain any responses on the back. FIG. 7 Patent Application Publication May 19, 2011 Sheet 14 of 33 US 2011/O118227 A1 Fibromyalgia Study. Testosterone Replacement Therapy vs Placebo Physician Questionnaire Eligibility Criteria Form Eligibility Criteria Patient Code Number Patient Initials .......... Prelim TP Exam Date Physician (initials): A. Laboratory tests for eligibility criteria Screen visit day 1 12 weeks 24 weeks Dale blood drawn (mm/dd/yy) f / f / f / --- l. Testosterone: ................................ 2. EStradiol: ....................................... 3. Lipid Profile. a total cholesterol ............................ b. HDL ......................................... C. D. ...................... 4. Liver Function Tests (LFT): a. All-T (Alanine aminotransferase) ammurum- o b. ALP (Alkaline phosphatase) ........ c. AST (Asp aminotransferase) ........ d. albumin ......................................... e. Til . f. DBill ............................................... 5. Kidney function: a. BUN . --- ---------- --mm b. creatinine ...................................... am ------------- --------- 6. FSH. --mm 7. CBC Flemoglobin.......................... ------------- - ----- B. Informed written consent obtained? Yes | No C. Does the patient express any Symptoms of chronic fatigue? D. Does the patient express difficulty obtaining restorative sleep? FIG. 8 Patent Application Publication May 19, 2011 Sheet 15 of 33 US 2011/O118227 A1 Fibromyalgia Study. Testosterone Replacement Therapy vs Placebo Dose Coordinato Serum Testosterone Values Patient Code Number... Patient Initials ............. Prelim TP Exam Date . f f Circle: Placebo Testosterone : Dose Coordinator (initials): 4 weeks 8 weeks l2 weeks l 6 weeks 20 weeks 24 weeks Date blood drawn f / A / f / f f f f / / A. Total Testosterone: B. Free Testosterone: Based on Free Testosterone: Step up packet? f / f / f / f / f f f / (if LOW free T s l.9pg/mL, date patient started change in Study gel dose) Step down packet? / / f / f / f / f f f f f (if High free T P 3.3 pg/mL, date patient started change in Study gel dose) FIG. 9 Patent Application Publication May 19, 2011 Sheet 16 of 33 US 2011/O118227 A1 SJLNIOdRIGH(INGHJ,SWH:JAVNOIAVOIJVÍ?TIÞÆGIAVVIOISÄHAI Patent Application Publication May 19, 2011 Sheet 17 of 33 US 2011/O118227 A1 Fibromyalgia Study. TestosterOne Replacement Therapy vs Placebo Physician General Health Form Patient Code Number Patient Initials .......... Exam Date ................. / / Circle One: Screening Visit 2 Week 2 Week 24 Physician (initials): LUNGS: CARDIOVASCULAR: ABDOMINAL: EDEMA: HEENT (Head Eyes Ears Nose Throat).